swissethics
Schweizerische Ethikkommissionen für die Forschung am Menschen
Commissions d’éthique suisses relative à la recherche sur l'être humain
Commissioni etiche svizzere per la ricerca sull'essere umano
Swiss Ethics Committees on research involving humans
Clinical Study Protocol (Study Title)
Study Identifier
Guiding version of the CTU Bern for the Swissethic’s protocol template
What follows is an exact match of the original MS Word template but with additional content, explanations, and
examples. In this guiding document additional comments and explanations are in italics/green. Examples from
existing studies are inserted as picture with grey background. Possible wordings are marked with “Example:”. In
some cases the suggested formulation is an alternative to the already provided suggestion by Swissethis.
Any suggestions are welcome and should be sent to info@unibe.ch.
This document is the Clinical Protocol template for IIT (Investigator initiated Trials) studies. AGEK
strongly recommends using this template to develop clinical research protocols for trials testing an
investigational medicinal product (IMP) or a medical device (MD) to be submitted to Swiss authorities.
This template is suitable for studies:
-
involving IIT,
performed in Switzerland, respectively where the Sponsor-Investigator is located in
Switzerland
where the study question does relate to the use of drug(s) or medical device effect(s),
where the Swiss law on therapeutic products (HMG/LPTh and Federal Act on Medicinal
Products and Medical Devices) applies,
where the Swiss law on human research (Federal Act on Research involving Human Beings
(HRA)) and its applicable ordinance ClinO/KlinV/OClin applies,
that are interventional*
*health related interventional studies include research in preventive, diagnostic, therapeutic, palliative
or rehabilitation activities that are examined in the context of a clinical trial.
The current template is based on:
-
-
AGEK – CT CER / Swissmedic guidelines: “Studienprotokolle von klinischen‚ Investigatorinitiated’ Studien/Versuchen / Exigences des protocoles d’études/d’essais cliniques initiés par
l’investigateur” dated 24.02.2009,
the Federal Act on Research involving Human Beings (HRA) and its applicable ordinance
(ClinO/KlinV/OClin)
the SPIRIT statement and
ICH-GCP E6, section 6
EN ISO14155:2011: Annex A
Swiss clinical trials portal (http://www.kofam.ch/en/swiss-clinical-trials-portal.html)
This template attempts to provide a general format applicable to all clinical trials evaluating an
investigational product (drugs or medical devices).
Note that instructions are indicated in blue italics and they need be deleted (or alternatively may be
formatted as “hidden Text” that will not show in printing).
Section headings and template text formatted in regular type red gives you reference to the legal
requirements. This text may be deleted.
Section headings and template text formatted in regular type (black) should be included in your protocol
document as provided in the template.
Header and footer should contain the following information (on all pages): [Protocol Title], [Page x of xx],
[version x, DD/MM/YYYY], [Study ID]
In places where the information is redundant, it is acceptable to reference another section, to document
or to state its redundancy but the section has not to be deleted.
Refer questions regarding use of this protocol template to swissethics/AGEK, info@swissethics.ch,
phone: +41 (41) 440 26 67, www.swissethics.ch.
Clinical Study Protocol
final V_01, 06.05.2014
Page 1 of 82
swissethics
Schweizerische Ethikkommissionen für die Forschung am Menschen
Commissions d’éthique suisses relative à la recherche sur l'être humain
Commissioni etiche svizzere per la ricerca sull'essere umano
Swiss Ethics Committees on research involving humans
This template was developed by a task force initiated by the Federal Office of Public Health (FOPH) and
the AGEK / CT CER during 2013 and under the lead and coordination of the Swiss Clinical Trial
Organisation (SCTO), Basel. Clinical research experts from 8 institutions reviewed the template. The
FOPH and AGEK reviewed the template and recommend its use.
Members of the task force no. 6 and contributors to this template:
-
FOPH, Dr Andri Christen
AGEK, Dr Wolfgang Tschacher
CTC Zurich, Dr Eva Brombacher
CTU St Gallen, Roger Getzmann
CTC Lausanne and Cochrane Switzerland, Dr Erik von Elm
CTC Geneva, Dr Christophe Combescure
EOC Ticino, Dr Liliane Petrini
SAKK, Dr Christiane Pilop
SCTO, Annette Magnin and Dr Caecilia Schmid
Reviewers:
-
EOC TI, Dr Claudio Gobbi
EOC TI, Dr Mauro Manconi
HUG: Prof. Dr Bernard Hirschel
HUG / EC: Dr Sandrine Charvat
Inselspital / Uni. Bern, Prof. Dr Peter Jüni, Dr Sven Trelle
KSSG, Prof. Dr Christoph Driessen
SAKK, Dr Pirus Ghadjar (Charité Berlin)
SPZ / EC Luzern, Dr Angela Frotzler
USZ, PD Dr Christian Baumann
USZ, Dr Cédric Poyet
Scienceindustries, Dr Daniela Gunz
Clinical Study Protocol
final V_01, 06.05.2014
Page 2 of 82
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<<Protocol template: Interventional study with
investigational medicinal product (IMP) / medical
device (MD)>>
Clinical Study Protocol
INSERT TITLE OF THE PROTOCOL
(AGEK 1; SPIRIT #1)
[Descriptive title identifying the study design (e.g. randomised, placebo controlled, etc.), aim, population (if
relevant), phase (if applicable, e.g. phase I, phase II...), target disease(s), the investigational drug or medical
device, and, if the study is multi-centred (-country)]
Example: A multi-center, investigator-blinded, randomized, 12-month, parallel-group, non-inferiority study to
compare the efficacy of 1.6 to 2.4 g Asacol® (once daily) versus divided dose (twice daily) in the maintenance
of remission of ulcerative colitis
SHORT TITLE and / or trial acronym / or translation (if relevant; title used in the informed consent)
Study Type:
Clinical trial with Investigational Medicinal Product (IMP), Medical
Device (MD)
Study Categorisation:
Risk category according to LHR (A, B or C)
Study Registration:
Name of WHO approved study registry (preferable clinicaltrials.gov)
(if not yet registered name the intended registry) and registration
number(s)
Study Identifier:
If additional identifier applies (e.g. institutional or Sponsor protocol
identifier)
Sponsor, Sponsor-Investigator or
Principal Investigator:
Name of Sponsor, Sponsor-Investigator or Principal Investigator
(any who is applicable)
Contact details (full details)
Investigational Product:
Study Drug – Generic, followed by marketed name if applicable;
Medical Device Name
Protocol Version and Date:
Version number and validity date
Add if applicable, the Amendment number, from (date), replaces
version number from (date)
CONFIDENTIAL
Add, if applicable, an institutional confidentiality statement here respecting that it is not in conflict with
applicable transparency rules. CTU Bern considers these confidentiality statements as unnecessary and
counterproductive.
e.g. “The information contained in this document is confidential and the property of the xx (or
“sponsor”). The information may not - in full or in part - be transmitted, reproduced, published, or
disclosed to others than the applicable Competent Ethics Committee(s) and Regulatory Authority(ies)
without prior written authorisation from the sponsor except to the extent necessary to obtain informed
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consent from those who will participate in the study.
Signature Page(s)
(AGEK 1.1; ICH E6 6.1)
ICH E6: Have signature pages with name and title of the person(s) authorised to sign the protocol and
the protocol amendment(s) for the sponsor or of the medical expert (if applicable), the investigator
responsible for conducting the trial (if not detailed in a contract), the statistician (if applicable)
Note: Add more lines, functions and pages if relevant, e.g. for trial statistician, if relevant or protocol
contributors. CTU Bern considers that all relevant contributors should be made explicit i.e. not only a
statistician. Add a table with names and corresponding sections for which the person contributed. The
Sponsor(-Investigator) has the final responsibility to authorize the protocol.
Study number
Study registry and registration number
Study Title
Full study title as written out on title page
The Sponsor-Investigator has approved the protocol version [x (dated DD.MM.YYYY)], and confirms
hereby to conduct the study according to the protocol, current version of the World Medical
Association Declaration of Helsinki, ICH-GCP guidelines or ISO 14155 norm if applicable and the
local legally applicable requirements.
Sponsor-Investigator:
Printed name of Sponsor-Investigator (if Sponsor and PI is not the same person please add an additional
signature line for the PI of the study)
Place/Date
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Local Principal Investigator at study site*:
I have read and understood this trial protocol and agree to conduct the trial as set out in this study
protocol, the current version of the World Medical Association Declaration of Helsinki, ICH-GCP
guidelines or ISO 14155 norm and the local legally applicable requirements.
Site
Name and address of site
Principal investigator
Printed name of Principal investigator
Place/Date
Signature
*Note: In multicentre studies, this page must be individually signed by all participating Local Principal
Investigators.
Maybe deleted if there are separate contracts for each site where adherence to the protocol is mentioned.
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Table of Contents
STUDY SYNOPSIS .............................................................................................................................9
STUDY SUMMARY IN LOCAL LANGUAGE CAN BE PROVIDED HERE (GERMAN, FRENCH OR
ITALIAN) .......................................................................................................................................... 12
ABBREVIATIONS ............................................................................................................................ 13
STUDY SCHEDULE ........................................................................................................................ 15
1.
STUDY ADMINISTRATIVE STRUCTURE ............................................................................... 17
1.1
Sponsor, Sponsor-Investigator ............................................................................................... 18
1.2
Principal Investigator(s) .......................................................................................................... 18
1.3
Statistician ("Biostatistician") ................................................................................................... 18
1.4
Laboratory ............................................................................................................................... 18
1.5
Monitoring institution ............................................................................................................... 19
1.6
Data Safety Monitoring Committee ......................................................................................... 19
1.7
Any other relevant Committee, Person, Organisation, Institution ........................................... 19
2.
ETHICAL AND REGULATORY ASPECTS ............................................................................. 21
2.1
Study registration .................................................................................................................... 21
2.2
Categorisation of study ........................................................................................................... 21
2.3
Competent Ethics Committee (CEC) ...................................................................................... 22
2.4
Competent Authorities (CA) .................................................................................................... 22
2.5
Ethical Conduct of the Study ................................................................................................... 23
2.6
Declaration of interest ............................................................................................................. 23
2.7
Patient Information and Informed Consent ............................................................................. 23
2.8
Participant privacy and confidentiality ..................................................................................... 24
2.9
Early termination of the study ................................................................................................. 24
2.10 Protocol amendments ............................................................................................................ 25
3.
BACKGROUND AND RATIONALE ......................................................................................... 27
3.1
Background and Rationale ...................................................................................................... 27
3.2
Investigational Product (treatment, device) and Indication ..................................................... 29
3.3
Preclinical Evidence ................................................................................................................ 29
3.4
Clinical Evidence to Date ........................................................................................................ 29
3.5
Dose Rationale / Medical Device: Rationale for the intended purpose in study (pre-market MD)
32
3.6
Explanation for choice of comparator (or placebo) ................................................................. 32
3.7
Risks / Benefits ....................................................................................................................... 32
3.8
Justification of choice of study population .............................................................................. 35
4.
STUDY OBJECTIVES .............................................................................................................. 36
4.1
Overall Objective ..................................................................................................................... 36
4.2
Primary Objective .................................................................................................................... 36
4.3
Secondary Objectives ............................................................................................................. 37
4.4
Safety Objectives .................................................................................................................... 37
5.
STUDY OUTCOMES ................................................................................................................ 38
5.1
Primary Outcome .................................................................................................................... 38
5.2
Secondary Outcomes ............................................................................................................. 38
5.3
Other Outcomes of Interest ..................................................................................................... 39
5.4
Safety Outcomes..................................................................................................................... 39
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6.
STUDY DESIGN ....................................................................................................................... 40
6.1
General study design and justification of design .................................................................... 40
6.2
Methods of minimising bias ..................................................................................................... 42
6.2.1 Randomisation ............................................................................................................... 42
6.2.2 Blinding procedures ....................................................................................................... 42
6.2.3 Other methods of minimising bias ................................................................................. 43
6.3
Unblinding Procedures (Code break) ..................................................................................... 43
7.
STUDY POPULATION ............................................................................................................. 45
7.1
Eligibility criteria ...................................................................................................................... 45
7.2
Recruitment and screening ..................................................................................................... 47
7.3
Assignment to study groups .................................................................................................... 47
7.4
Criteria for withdrawal / discontinuation of participants........................................................... 48
8.
STUDY INTERVENTION .......................................................................................................... 50
8.1
Identity of Investigational Products (treatment / medical device) ........................................... 50
8.1.1 Experimental Intervention (treatment / medical device) ................................................ 50
8.1.2 Control Intervention (standard/routine/comparator treatment / medical device) ........... 50
8.1.3 Packaging, Labelling and Supply (re-supply) ................................................................ 50
8.1.4 Storage Conditions ........................................................................................................ 51
8.2
Administration of experimental and control interventions ....................................................... 51
8.2.1 Experimental Intervention .............................................................................................. 52
8.2.2 Control Intervention ........................................................................................................ 53
8.3
Dose / Device modifications .................................................................................................... 53
8.4
Compliance with study intervention ........................................................................................ 53
8.5
Data Collection and Follow-up for withdrawn participants ...................................................... 53
8.6
Trial specific preventive measures.......................................................................................... 54
8.7
Concomitant Interventions (treatments) .................................................................................. 54
8.8
Study Drug / Medical Device Accountability ........................................................................... 54
8.9
Return or Destruction of Study Drug / Medical Device ........................................................... 54
9.
STUDY ASSESSMENTS.......................................................................................................... 55
9.1
Study flow chart(s) / table of study procedures and assessments ......................................... 55
9.2
Assessments of outcomes .........................................................................................................2
9.2.1 Assessment of primary outcome ......................................................................................2
9.2.2 Assessment of secondary outcomes ................................................................................2
9.2.3 Assessment of other outcomes of interest........................................................................2
9.2.4 Assessment of safety outcomes .......................................................................................2
9.2.5 Assessments in participants who prematurely stop the study ..........................................4
9.3
Procedures at each visit .............................................................................................................5
9.3.1 Split into subtitles by type of visit ......................................................................................5
9.3.2 Split into subtitles by type of visit ......................................................................................5
9.3.3 Split into subtitles by type of visit ......................................................................................5
10. SAFETY .......................................................................................................................................6
10.1 Drug studies ..............................................................................................................................6
10.1.1 Definition and assessment of (serious) adverse events and other safety related events 6
10.1.2 Reporting of serious adverse events (SAE) and other safety related events ...................7
10.1.3 Follow up of (Serious) Adverse Events .............................................................................8
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10.2 Medical Device Category C studies ..........................................................................................9
10.2.1 Definition and Assessment of (Serious) Adverse Events and other safety related
events 9
10.2.2 Reporting of (Serious) Adverse Events and other safety related events ....................... 10
10.2.3 Follow up of (Serious) Adverse Events .......................................................................... 10
10.3 Medical Device Category A studies ....................................................................................... 11
10.3.1 Definition and Assessment of safety related events ...................................................... 11
10.3.2 Reporting of Safety related events ................................................................................ 11
11. STATISTICAL METHODS........................................................................................................ 12
11.1 Hypothesis.............................................................................................................................. 12
11.2 Determination of Sample Size................................................................................................ 12
11.3 Statistical criteria of termination of trial .................................................................................. 15
11.4 Planned Analyses .................................................................................................................. 15
11.4.1 Datasets to be analysed, analysis populations .............................................................. 15
11.4.2 Primary Analysis ............................................................................................................ 15
11.4.3 Secondary Analyses ...................................................................................................... 15
11.4.4 Interim analyses ............................................................................................................. 15
11.4.5 Safety analysis ............................................................................................................... 17
11.4.6 Deviation(s) from the original statistical plan ................................................................. 17
11.5 Handling of missing data and drop-outs ................................................................................ 17
12. QUALITY ASSURANCE AND CONTROL ............................................................................... 18
12.1 Data handling and record keeping / archiving........................................................................ 18
12.1.1 Case Report Forms........................................................................................................ 19
12.1.2 Specification of source documents ................................................................................ 19
12.1.3 Record keeping / archiving ............................................................................................ 19
12.2 Data management .................................................................................................................. 20
12.2.1 Data Management System ............................................................................................ 20
12.2.2 Data security, access and back-up ................................................................................ 20
12.2.3 Analysis and archiving ................................................................................................... 20
12.2.4 Electronic and central data validation ............................................................................ 21
12.3 Monitoring............................................................................................................................... 21
12.4 Audits and Inspections ........................................................................................................... 21
12.5 Confidentiality, Data Protection .............................................................................................. 22
12.6 Storage of biological material and related health data ........................................................... 22
13. PUBLICATION AND DISSEMINATION POLICY .................................................................... 23
14. FUNDING AND SUPPORT ...................................................................................................... 24
14.1 Funding .................................................................................................................................. 24
14.2 Other Support ......................................................................................................................... 24
15. INSURANCE ............................................................................................................................. 24
16. REFERENCES.......................................................................................................................... 25
17. APPENDICES ........................................................................................................................... 26
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STUDY SYNOPSIS
Ensure that the synopsis exactly matches to the main protocol (including front page) and the German
translation. It is recommended that the synopsis is written after the main protocol is finalized.
The study synopsis should be detailed enough to allow (ethical) judgement of the trial.
(ClinO, Appendix 3, 1.1, 2.1, 3.1, 4.1; Appendix 5, 2b; AGEK Summary)
Provide a structured synopsis containing all important information, preferably in tabular view:
Sponsor / SponsorInvestigator
Name of Sponsor / Sponsor-Investigator
Example: Prof. Dr. Martina Trialist
Department of Clinical Trials
Inselspital, Bern University Hospital
CH-3010 Bern
Switzerland
Study Title:
Full title of protocol
Short Title / Study
ID:
Short title of protocol or Study ID, if applicable
Protocol Version and
Date:
The version number and the date of the valid study protocol.
Trial registration:
Provide the name of the study registry and the registration number and date
(if not registered then indicate the anticipated registry)
Study category and
Rationale
Provide the determined study category with explanation for this category
Clinical Phase:
For clinical trials with drugs: Clinical study phase or phase of clinical
development (e.g. Phase 1, 2, 3 or 4; or according to ICH E8 para 3.1.3
Human Pharmacology, Therapeutic Exploratory, Therapeutic Confirmatory or
Therapeutic Use); in case of Medical Device study rename and use e.g.
“Phase of development”
Background and
Rationale:
Provide a short background and the rationale for the study, this includes the
health condition studied
Objective(s):
Brief statement of primary study objectives and the main secondary study
objectives.
Primary objectives
Example: To assess whether intervention X improves survival in patients with
disease D as compared to intervention Y
Secondary objectives
Example: To assess the adverse effects of intervention X as compared to
intervention Y in patients with disease D
Outcome(s):
Brief statement of primary study outcome and the main secondary study
outcome measures.
Primary outcomes
Example: Overall survival defined as time from randomization to death or last
follow-up available
Secondary outcomes
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Study design:
Design attributes such as open label; randomised, placebo or active control;
cross-over design, etc.
Example: This trial is an international, multicentre, open-label, two-arm,
parallel-group, randomized-controlled trial.
Inclusion / Exclusion
criteria:
Brief description of the anticipated study population, the key inclusion and
exclusion criteria and if applicable, the reasons for inclusion of vulnerable
participants
Do not list all but only the most important ones
Measurements and
procedures:

List criteria that describe the overall nature of the population of
interest

Signed informed consent with understanding of the study procedures
and the investigational nature of the study

List criteria that exclude patients from the study although inclusion
criteria are met e.g. specific laboratory values

Pregnant or nursing women

Known intolerance to any protocol intervention

Participation in another clinical trial

Patient's lack of accountability, inability to appreciate the nature,
meaning and consequences of the study and to formulate his/her
own wishes correspondingly
Describe the study intervention (methodology, procedures, sampling if
applicable) Note that this section is not about the study intervention but the
(study-specific) assessments and procedures
Example: Outcomes will be assessed every other month over the first six
months using postal questionnaires. In case of non-response outcomes will be
assessed via telephone interviews.
Study Product /
Intervention:
Describe the study specific intervention (product (drug / device name
(generic), dose, route, regimen) used in the study). Duration of product
administration (also run-in if applicable)
Intervention I (name, dose, route of administration, frequency, duration)
Intervention II (name, dose, route of administration, frequency, duration)
Intervention III (name, dose, route of administration, frequency, duration)
Control Intervention
(if applicable):
Describe if applicable the comparator(s) (e.g. active control, reference
therapy, placebo)
Number of
Participants with
Rationale:
Number of participants projected for the entire study (e.g. not for simply one
site, rather for entire study, all sites combined). Give the total and the
numbers for each treatment group.
Example: The proposed trial is a superiority trial. We assume a mean baseline
score on the NCCN distress thermometer of around 3.5 with a standard
deviation of 2.5 and a difference between groups of 1 point as clinically
relevant. Based on a repeated measures ANCOVA (correcting for baseline
values), a power of 90% and a two-sided alpha of 0.05 we calculated a
required sample size of 55 patients per group. To account for drop-outs and
losses to follow-up we set the final sample size to 75 per group or 150
patients overall.
Study Duration:
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Estimated duration for the main investigational plan (e.g. from start of
screening of first participant to last participant processed and finishing the
study)
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Study Schedule:
Month Year of First-Participant-In (planned)
Month Year of Last-Participant-Out (planned)
Investigator(s):
First patient in:
dd.mm.yyyy
Last patient in:
dd.mm.yyyy
Last patient out:
dd.mm.yyyy
Interim analyses:
dd.mm.yyyy
Database closure:
dd.mm.yyyy
Statistical analysis:
dd.mm.yyyy
Study report:
dd.mm.yyyy
Name(s) of Investigator(s)
Full contact details
Example: Investigators will be documented in the trial master file
Study Centre(s):
Single-centre or multi-centre. If multi-centre note number of projected centres
to be involved. Or countries if multi-national study
Statistical
Considerations:
A very brief description of the main elements of the statistical methodology to
be used in the study. Explanation to sample size
Example: Survival time will be compared between groups using Kaplan-Meier
curves and a Cox proportional hazards model. Adverse events will be
described using descriptive statistics.
GCP Statement:
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This study will be conducted in compliance with the protocol, the current
version of the Declaration of Helsinki, the ICH-GCP or ISO EN 14155
(as far as applicable) as well as all national legal and regulatory
requirements.
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STUDY SUMMARY IN LOCAL LANGUAGE
Ensure that the “Zusammenfassung” exactly matches to the main protocol (including front page) and the
English summary. It is suggested that the German translation is done as the final step (after the English
summary was written).
The lay summary in the local language may be provided here (German, French or Italian)
Sponsor:
Principal Investigator
Studientitel
PrüferInnen
Eine Liste aller PrüferInnen wird im Trial Master File ausgewiesen.
Studienzentren
Eine Liste aller Studienzentren wird im Trial Master File ausgewiesen
Zeitplan
Einschluss erster Patient: dd.mm.yyyy
Einschluss letzter Patient: dd.mm.yyyy
Studienende letzter Patient:
dd.mm.yyyy
Interimanalysen: dd.mm.yyyy
Abschluss Datenbank:
dd.mm.yyyy
Statistische Analyse:
dd.mm.yyyy
Studienreport:
Studienziele
dd.mm.yyyy
Primäre Studienziele
Sekundäre Studienziele
Design
Anzahl Studienteilnehmer
Haupteinschlusskriterien
Interventionen
Nachbeobachtung/
Untersuchungen
Endpunkte
Primäre Endpunkte
Sekundäre Endpunkte
Statistische Analyse
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ABBREVIATIONS
Provide a list of abbreviations used on the protocol - to be completed
AE
Adverse Event
CA
Competent Authority (e.g. Swissmedic)
CEC
Competent Ethics Committee
CRF
Case Report Form
ClinO
Ordinance on Clinical Trials in Human Research (in German: KlinV, in French: OClin)
eCRF
Electronic Case Report Form
CTCAE
Common terminology criteria for adverse events
DSUR
Development safety update report
GCP
Good Clinical Practice
IB
Investigator’s Brochure
Ho
Null hypothesis
H1
Alternative hypothesis
HFG
Humanforschungsgesetz (Law on human research)
HMG
Heilmittelgesetz
HRA
Federal Act on Research involving Human Beings
IMP
Investigational Medicinal Product
IIT
Investigator-initiated Trial
ISO
International Organisation for Standardisation
ITT
Intention to treat
KlinV
Verordnung über klinische Versuche in der Humanforschung (in English: ClinO, in
French OClin)
LPTh
Loi sur les produits thérapeutiques
LRH
Loi fédérale relative à la recherche sur l’être humain
MD
Medical Device
OClin
Ordonnance sur les essais cliniques dans le cadre de la recherche sur l'être humain (in
German : KlinV, in English : ClinO)
PI
Principal Investigator
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SDV
Source Data Verification
SOP
Standard Operating Procedure
SPC
Summary of product characteristics
SUSAR
Suspected Unexpected Serious Adverse Reaction
TMF
Trial Master File
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STUDY SCHEDULE
(AGEK 4.2; SPIRIT #13; ICH E6 6.4.2)
Insert a flow chart (graphic) or tabular listing of schedule of events and assessments and procedures of the
study (an example is provided below, amend and expand according to the specific study). To be repeated in
9.1.
e.g.:
Study Periods
Screening
Treatment, Intervention Period
Followup
Visit
1
2
3
4
5
6
Time (hour, day, week)
-7
0
1
8+/-1d
15+/-2d
22
Patient Information and
Informed Consent
x
Demographics
x
Medical History
x
In- /Exclusion Criteria
x
Physical Examination
x
Vital Signs
x
Laboratory Tests
x
Pregnancy Test
x
x
x
x
x
x
x
x
x
x
(x)
Randomisation
x
Other examinations, tests…
x
Other examinations, tests…
x
x
Administer Study Medication,
Medical Device
x
x
x
x
x
Primary Variables
x
x
x
x
x
x
Secondary Variables
x
x
x
x
x
x
Concomitant Therapy,
Intervention
x
x
x
x
Adverse Events
x
x
x
x
x
Study time schedule
First patient in:
dd.mm.yyyy
Last patient in:
dd.mm.yyyy
Last patient out:
dd.mm.yyyy
Interim analyses:
dd.mm.yyyy
Database closure:
dd.mm.yyyy
Statistical analysis:
dd.mm.yyyy
Study report:
dd.mm.yyyy
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EXAMPLE: PVAG-14 pilot trial
Time schedule
First patient in:
01.04.2006
Inclusion last patient (Randomization):
30.11.2007
Interim analysis:
31.05.2007
Analysis of primary endpoints:
31.08.2008
Last patient out (end of 5-year follow up):
31.05.2013
Final statistical analysis:
30.11.2013 (final analysis)
Study report:
31.12.2013
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1. STUDY ADMINISTRATIVE STRUCTURE
(ICH/E6 6.1.2-6.1.7; AGEK 1.1; SPIRIT 5a-d)
Any committee(s) to be formed should be mentioned here (e.g., safety committees, data monitoring
committees, etc.). Subsections may be expanded if necessary but shall not be deleted if not relevant.
Describe a solution, if not all personnel involved are determined at this stage and may be referred to other
documents than the protocol.
Provide complete contact details (address, phone, fax numbers, e-mail) of all individuals or groups/committees
and their composition, roles, and responsibilities overseeing the trial (e.g. Sponsor, PI, statistician, monitor,
coordinator, any committee, data management team, and other individuals or groups, laboratories if
applicable).
Describe the general organization of the study i.e. number of centers, types of centers/settings, coordination,
data management, etc.
EXAMPLE
Organization of the study
This multicenter trial is centrally coordinated by CTU Bern and conducted in 56 tertiary care
centers in Switzerland, France, Germany, and Italy.
A Data (and Safety) Monitoring Board/Committee is a group of independent experts who monitor aspects of a
study while it is running. Most often safety data is monitored but other aspects such as efficacy data,
recruitment, overall quality of the study performance, center-specific performance might also be monitored by
the DSMB. Note that the DSMB acts independently from the sponsor or any other study organization (such as
the steering committee) and provides recommendations but no decisions. The final responsibility for the study
remains always with the sponsor. Describe organization, participants, responsibilities and procedures. Data
and safety monitoring is closely related to interim analyses and requires a detailed statistical analysis
approach.
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EXAMPLE: RECORD trial
The Data Monitoring Committee
A data monitoring committee will be established. This will be independent of the trial organisers.
During the period of recruitment to the trial, interim analyses will be supplied, in strict confidence,
to the data monitoring committee, together with any other analyses that the committee may
request. This may include analyses of data from other comparable trials. In the light of these
interim analyses, the data monitoring committee will advise the Steering Committee if, in its view,
one or more of the randomised comparisons in the trial has provided both (a) proof beyond
reasonable doubt1 that for all or some types of patients one particular type of intervention is
clearly indicated in terms of a net reduction in fracture risk without any increased risk of death (or
clearly contraindicated because of a net increase in fracture risk or mortality), and (b) evidence
that might reasonably be expected to influence materially the care of people who sustain a
fracture by clinicians who know the results of this and comparable trials. The Steering Committee
can then decide whether or not to modify intake to the trial. Unless this happens, however, the
steering committee, project management group, clinical collaborators, and trial office staff
(except those who supply the confidential analyses) will remain ignorant of the interim results.
The frequency of interim analyses will depend on the judgement of the chairman of the
committee, in consultation with the Steering Committee. Initially, the principal concern will be
possible adverse effects. Data on new fractures will accumulate slowly so the committee is
unlikely to be able to consider these reliably until some way into the trial.
Appropriate criteria for proof beyond reasonable doubt cannot be specified precisely. A difference of at least three
standard deviations in the interim analysis of a major endpoint may be needed to justify halting, or modifying, such a
study prematurely. If this criteria were to be adopted, it would have the practical advantage that the exact number of
interim analyses would be of little importance, and so no fixed schedule is proposed (Peto R et al. Br J Cancer 1976;
34: 584-612).
1
1.1
Sponsor, Sponsor-Investigator
(ICH/E6 6.1.2; AGEK 1.1; SPIRIT 5b)
ICH: Name and address of the sponsor …..
Provide the complete contact details of the Sponsor, its role in the study; its role in the study design;
collection, management, analysis, and interpretation of data; writing of the report;
If applicable, this may also include legal representative(s) in foreign countries, in case of a multi-national study
with a Swiss Sponsor-Investigator.
Name:
Address:
Tel:
E-mail:
1.2
Principal Investigator(s)
(ICH/E6 6.1.5, 6.1.6; AGEK 1.1; SPIRIT 5a-d)
ICH: Name and title of the investigator(s) who is (are) responsible for conducting the trial, and the
address and telephone number(s) of the trial site(s).
Name, title, address, and telephone number(s) of the qualified physician (or other qualified person, if
applicable), who is responsible for all trial-site related medical decisions (if other than investigator).
Provide the complete contact details of the investigator(s) or reference to where a list of investigators and
study sites can be obtained (some can be covered in contracts)
Name:
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Address:
Tel:
E-mail:
1.3
Statistician ("Biostatistician")
(ICH/E6 6.1.7; SPIRIT 5a-d)
ICH: Name(s) and address(es) of the clinical laboratory(ies) and other medical and/or technical
department(s) and/or institutions involved in the trial.
Name, title, address, email and telephone number(s) of the qualified statistician involved in the trial.
Name:
Address:
Tel:
E-mail:
1.4
Laboratory
(ICH/E6 6.1.7; SPIRIT 5a-d)
ICH: Name(s) and address(es) of the clinical laboratory(ies) …………. involved in the trial.
Provide if applicable the name of the laboratory that is involved in the trial (may be referred to different
document, e.g. separate agreement).
1.5
Monitoring institution
(ICH/E6 6.1.2; SPIRIT 5a-d)
ICH: Name and address of the …. monitor (if other than the sponsor).
Provide the name of the institution, place and country that monitors the study, if other than the Sponsor (may
be referred to different document, e.g. separate agreement).
Responsible for study site:
Name:
Address:
Tel:
E-mail:
1.6
Data Safety Monitoring Committee
(ICH/E6 6.1.7; SPIRIT 5a-d)
ICH: Name(s) and address(es) of the clinical laboratory(ies) and other medical and/or technical
department(s) and/or institutions involved in the trial.
(if applicable, also for MD pre-market products)
If applicable this should comprise the composition of data safety monitoring committee (DSMC); summary of
its role and reporting structure; statement of whether it is independent from the Sponsor and competing
interests; and reference to where further details about its charter can be found, if not in the protocol.
Alternatively, provide an explanation of why a DSMC is not needed.
Data management
Name:
Address:
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Tel:
E-mail:
1.7
Any other relevant Committee, Person, Organisation, Institution
(ICH/E6 6.1.7; SPIRIT 5a-d)
ICH: Name(s) and address(es) of the clinical laboratory(ies) and other medical and/or technical
department(s) and/or institutions involved in the trial.
If applicable e.g. study coordination, data management, etc. Alternatively, write “not applicable”.
Trial coordination/management
Name:
Address:
Tel:
E-mail:
Drug supply
Name:
Address:
Tel:
E-mail:
A steering committee/board is usually responsible for the scientific oversight of a study e.g. was responsible
for the initiation of the study, wrote (main parts of) the protocol, decides about amendments. Describe general
organization, members, responsibilities, etc.
EXAMPLE: RECORD trial
The Steering Committee
The trial is supervised by an MRC Steering Committee. This is made up of three independent
members selected by the MRC, together with those originally granted funds to mount the trial.
Observers from the MRC and host university (University of Aberdeen) may also attend. Other
members of the Project Management Group may attend as observers at the invitation of the
Chair of the Steering Committee.
Describe the study coordination including all tasks centrally coordinated
EXAMPLE: RECORD trial
The Trial Office
The Trial Office is in the Health Services Research Unit at Aberdeen and gives day to day
support to the clinical centres. It is responsible for collection of data (in collaboration with the
local study nurses), data processing and analysis. It is also responsible for randomisation,
despatch of trial materials to participants, and unblinding, as clinically necessary.
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EXAMPLE: CRASH trial
Co-ordinating Centre responsibilities
•
Provide study materials and a 24-hour randomisation (and unblinding) service (Figure 5)
•
Give collaborators regular information about the progress of the study
•
Help ensure complete data collection at discharge and at six months
•
Respond to any questions (e.g. from collaborators) about the trial
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2. ETHICAL AND REGULATORY ASPECTS
(ICH/E6 6.12; AGEK 11; SPIRIT #24, 5)
ICH: Description of ethical considerations relating to the trial.
Before the study will be conducted, the protocol, the proposed patient information and consent form as well as
other study-specific documents shall be submitted to a properly constituted Competent Ethics Committee
(CEC) and/or competent authorities (name the authority, e.g. Swissmedic / FOPH / foreign competent
authorities; Note that clinical studies of category A do not need a Swissmedic approval, please delete
respective passage) in agreement with local legal requirements, for formal approval. Any amendment to the
protocol must as well be approved (if legally required) by these institutions.
The decision of the CEC and Swissmedic/foreign competent authority concerning the conduct of the
study will be made in writing to the Sponsor-Investigator before commencement of this study. The
clinical study can only begin once approval from all required authorities has been received. Any
additional requirements imposed by the authorities shall be implemented.
Example: This trial is conducted in accordance with the Declaration of Helsinki {World Medical Association,
2008 #2}, the International Conference on Harmonization Good Clinical Practice Guidelines (ICH-GCP)
{International Conference on Harmonisation, 1996 #1} and all applicable national and cantonal laws.
Example: The participating investigators/institutions permit study-related monitoring, audits, independent
ethics committee (IEC) review, and regulatory inspections and provide direct access to source
documents/data.
2.1
Study registration
(ClinO, Art. 1d, 64; SPIRIT #2a-b)
Provide a statement of study registration, where it is, or is intended to be, registered, include the number and
date; include further registrations if registered in other registries.
The study should be registered in a registry listed in the WHO International Clinical Trials Registry Platform
(ICTRP, http://www.who.int/ictrp/en/). In addition, registration in a national language in the Swiss Federal
Complementary Database (Portal) is required.
Example: The sponsor ensures that the study is registered in a WHO approved clinical study register,
preferably at clinicaltrials.gov, before participant recruitment in the study starts.
2.2
Categorisation of study
(ClinO, Art. 19, 20, App 3, 1.1)
Describe the risk category and the rationale for the categorisation;
Article 19 Categorisation of clinical trials of medicinal products
1
Clinical trials of medicinal products come under Category A if the medicinal product is authorised in
Switzerland and its use:
a.
is in accordance with the prescribing information;
b.
is in an indication or dosage different from that specified in the prescribing information, but in
accordance with the following criteria:
1. the indication is within the same disease group of the International Classification of Diseases
(ICD), as specified in Annex 1, number 3,
2. the disease in question is self-limiting and the dosage of the medicinal product lower than that
specified in the prescribing information; or
c.
2
is recognised as standard in guidelines prepared in accordance with internationally accepted
quality criteria.
Clinical trials of medicinal products come under Category B if the medicinal product:
a.
is authorised in Switzerland; and
b.
is not used as specified in paragraph 1.
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3
They come under Category C if the medicinal product is not authorised in Switzerland.
4
In justified cases, a clinical trial of a medicinal product authorised in Switzerland may be assigned to a
different category if this is possible or necessary with regard to medicinal product safety or protection of the
participants’ safety and health.
Article 20 Categorisation of clinical trials of medical devices
1
2
Clinical trials of medical devices come under Category A if:
a.
the medical device bears a conformity marking; and
b.
it is used in accordance with the instructions.
They come under Category C if:
a.
the medical device does not have a conformity marking;
b.
it is not used in accordance with the intended purposes recognised in the conformity assessment
and specified in the instructions; or
c.
use of the medical device is prohibited in Switzerland.
Example: This study is considered to fall under category A/B/C according to HFV-1/2.
Provide evidence and justification for categorization. Provide sound evidence in case of downgrading.
2.3
Competent Ethics Committee (CEC)
(ClinO, Art 24-29; SPIRIT #24)
Mention that the responsible investigator at each site ensures that approval from an appropriately constituted
Competent Ethics Committee (CEC) is sought for the clinical study.
Mention the reporting duties and allowed time frame (all changes in the research activity and all unanticipated
problems involving risks to humans; including in case of planned or premature study end and the final report)
and that no changes are made to the protocol without prior Sponsor and CEC approval, except where
necessary to eliminate apparent immediate hazards to study participants.
Premature study end or interruption of the study is reported within 15 days. The regular end of the study is
reported to the CEC within 90 days, the final study report shall be submitted within one year after study end.
Amendments are reported according to chapter 3.10.
Example: The responsible investigator at each site ensures that an appropriately constituted independent
ethics committee (IEC) is responsible for the initial and continuing review and approval of the clinical study.
Before initiation of the study, the investigator forwards copies of the protocol, consent form and any other
required document to the IEC for its review and approval.
Example: The investigator ensures that all changes in the research activity and all unanticipated problems
involving risks to human subjects are reported promptly to the IEC, and that no changes are made to the
protocol without prior sponsor and IEC approval, except where necessary to eliminate apparent immediate
hazards to study participants.
2.4
Competent Authorities (CA)
(ClinO, Art. 23, 27, 30-39, 42, 43, 46-48, 57; SPIRIT #24)
Mention that the Sponsor will obtain approval from the competent authority (e.g. Swissmedic) before the start
of the clinical trial. CA approval is necessary for all studies category B and C (IMP and MD).
Mention the reporting duties and allowed time frame to CA including the reporting duties in case of planned or
premature study end and the final report. Reporting duties and timelines are the same as for CEC, except of
non-substantial amendments that shall be reported as soon as possible. Amendments are reported according
to chapter 3.10.
Add other local requirements in case of international studies.
Example: The sponsor ensures that the clinical study is approved by all relevant cantonal ethics committees
and Swissmedic according to local laws.
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2.5
Ethical Conduct of the Study
(ClinO, Art. 5; AGEK 11; ICH E6 6.12, 6.2.5)
ICH: A statement that the trial will be conducted in compliance with the protocol, GCP and the applicable
regulatory requirement(s).
The study will be carried out in accordance to the protocol and with principles enunciated in the
current version of the Declaration of Helsinki, the guidelines of Good Clinical Practice (GCP) issued
by ICH, in case of medical device: the European Directive on medical devices 93/42/EEC and the
ISO Norm 14155 and ISO 14971, the Swiss Law and Swiss regulatory authority’s requirements. The
CEC and regulatory authorities will receive annual safety and interim reports and be informed about
study stop/end in agreement with local requirements.
Add other local requirements in case of medical device or international studies.
Example: The participating investigators/institutions permit study-related monitoring, audits, independent
ethics committee (IEC) review, and regulatory inspections and provide direct access to source
documents/data.
2.6
Declaration of interest
(ClinO, Art. 3b; SPIRIT #28)
Declare any conflict of interest if applicable, otherwise provide a statement of no conflict of interest
(independence, intellectual, financial, proprietary etc)
2.7
Patient Information and Informed Consent
(ClinO, Art. 7-9, Art. 15-17, Appendix 3, 1.4, 2.4, 3.4, 4.3, Appendix 4, 3.6; AGEK submission checklist
item 5; SPIRIT #26, 32)
Explain that participants will be informed about the study (what, how, by whom) and that consent is sought
from each participant (e.g. sample text below); include the mention of compensation if any; describe special
approaches in case of vulnerable population (e.g. children assent). Describe the process specific to the trial
(see also HFG and respecting ordinances KlinV/OClin para 7-9).
e.g. The investigators will explain to each participant the nature of the study, its purpose, the
procedures involved, the expected duration, the potential risks and benefits and any discomfort it
may entail. Each participant will be informed that the participation in the study is voluntary and that
he/she may withdraw from the study at any time and that withdrawal of consent will not affect his/her
subsequent medical assistance and treatment.
The participant must be informed that his/her medical records may be examined by authorised
individuals other than their treating physician.
All participants for the study will be provided a participant information sheet and a consent form
describing the study and providing sufficient information for participant to make an informed decision
about their participation in the study. Enough time needs to be given to the participant to decide whether to
participate or not. Please specify the time frame given.
The patient information sheet and the consent form will be submitted to the CEC and to the
competent authority (as applicable) to be reviewed and approved. The formal consent of a participant,
using the approved consent form, must be obtained before the participant is submitted to any study
procedure.
The participant should read and consider the statement before signing and dating the informed
consent form, and should be given a copy of the signed document. The consent form must also be
signed and dated by the investigator (or his designee) and it will be retained as part of the study
records.
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Example: The investigator assumes the responsibility of obtaining written informed consent for each
participant before any study-specific procedures are performed and before any study intervention is
administered.
Example: Persons meeting the criteria set forth in the protocol are offered the opportunity to participate in the
study. To avoid introduction of bias, the investigator must exercise no selectivity with regard to offering eligible
persons the opportunity to participate in the study. Eligible persons or parents/legal guardians of candidate
persons receive a comprehensive explanation of the proposed treatment, including the nature of the therapy,
alternative therapies available, any known previously experienced adverse reactions, the investigational status
of the study interventions, and other factors that are part of obtaining a proper informed consent. Persons are
given the opportunity to ask questions concerning the study, and adequate time to consider their decision
whether to or not to participate.
Example: Informed consent is documented by the use of a written consent form that includes all the elements
required by regulations and as approved by the relevant ethics committee. The form is to be signed and dated
by the participant or participant's legally authorized representative and by the person who administers the
consent process. A copy of the signed form is given to the person who signed it, the original signed consent
form is filed in the investigator site file An additional copy may be filed in the participant's medical chart. The
following information must be recorded in the source documents:

Date and time of the informed consent interview including any agreements if applicable e.g.
participant will come back next day with a decision

Confirmation that participant received the written participant information

Any witnesses if applicable

Any other information that seems important
Example: Persons can make a free decision on participation in the study at any time. If study participation is
refused, the choice of treatment is at the discretion of the study participant.
2.8
Participant privacy and confidentiality
(ClinO, Art. 18; ICH/E6 6.10; AGEK 12.2, SPIRIT #27)
ICH: The sponsor should ensure that it is specified in the protocol or other written agreement that the
investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, and regulatory
inspection(s), providing direct access to source data/documents.
The investigator affirms and upholds the principle of the participant's right to privacy and that they
shall comply with applicable privacy laws. Especially, anonymity of the participants shall be
guaranteed when presenting the data at scientific meetings or publishing them in scientific journals.
Individual subject medical information obtained as a result of this study is considered confidential
and disclosure to third parties is prohibited. Subject confidentiality will be further ensured by utilising
subject identification code numbers to correspond to treatment data in the computer files.
For data verification purposes, authorised representatives of the Sponsor (-Investigator), a
competent authority (e.g. Swissmedic), or an ethics committee may require direct access to parts of
the medical records relevant to the study, including participants’ medical history.
Example: The investigator affirms and upholds the principle of the participant's right to privacy. Investigators
shall comply with applicable privacy laws.
Example: The written informed consent form will explain that the study data will be stored in a computer
database, maintaining confidentiality in accordance with local data legislation. Subjects in this database will be
identified by participant identifier or pseudonym. The participant information will also explain that for data
verification purposes, authorized representatives of the sponsor, a regulatory authority, or an ethics committee
may require direct access to parts of the medical records relevant to the study, including participants’ medical
history.
Example: Especially, anonymity of the participants will be guaranteed when presenting the data at scientific
meetings or publishing them in scientific journals.
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2.9
Early termination of the study
(ClinO Art. 47; ICH/E6 6.4.6; SPIRIT #21b)
ICH: A description of the "stopping rules" or "discontinuation criteria" for individual participants, parts
of trial and entire trial.
Provide a statement that the Sponsor-Investigator (and any competent authority) may terminate the study
prematurely according to certain circumstances (name the reasons).
The Sponsor-Investigator may terminate the study prematurely according to certain circumstances,
for example:





ethical concerns,
insufficient participant recruitment,
when the safety of the participants is doubtful or at risk, respectively,
alterations in accepted clinical practice that make the continuation of a clinical trial unwise,
early evidence of benefit or harm of the experimental intervention
Describe procedures when formal stopping rules are met if not described above
2.10 Protocol amendments
(ClinO, Art. 29, 34, 55; SPIRIT #25)
State, who is allowed to amend the protocol or to provide suggestions for a protocol amendment. Provide
plans for communicating important protocol modifications (e.g., changes to eligibility criteria, outcomes,
analyses) to relevant parties (e.g., investigators, CEC, competent authorities, trial participants, trial registries,
journals, regulators).
Substantial amendments are only implemented after approval of the CEC and CA respectively.
Under emergency circumstances, deviations from the protocol to protect the rights, safety and wellbeing of human subjects may proceed without prior approval of the sponsor and the CEC/CA. Such
deviations shall be documented and reported to the sponsor and the CEC/CA as soon as possible.
All Non-substantial amendments are communicated to the CA as soon as possible if applicable and
to the CEC within the Annual Safety Report (ASR).
Example: In order to maintain comparable conditions in all study sites and to obtain an unobjectionable data
analysis changes of the protocol are not intended. If nonetheless changes become necessary they are
reported as amendment.
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Example: Any change or addition to this protocol requires a written protocol amendment that must be
approved by the study sponsor before implementation. Amendments affecting the safety of participants, the
scope of the investigation or the scientific quality of the study, require additional full approval by the IEC of all
sites, and by regulatory authorities. Examples of amendments requiring such approval are:

Increase in intervention dosage or duration of exposure of participants

Changes in the study design

Increase in the number of invasive procedures to which participants are exposed

Addition or deletion of a test procedure for safety monitoring
Example: The requirements for approval should in no way prevent any immediate action from being taken by
the investigator or the study sponsor in the interests of preserving the safety of all participants included in the
study. If an immediate change to the protocol is felt to be necessary by the investigator and is implemented by
him/her for safety reasons the study sponsor should be notified immediately and the IEC at the centre should
be informed within ten working days.
Example: Amendments affecting only administrative aspects of the study do not require formal protocol
amendments or IEC approval but the IEC of each site must be kept informed of such administrative changes.
Examples of administrative changes not requiring formal protocol amendments and IEC approval that can be
treated as administrative amendments include but are not limited to:

Changes in the staff used to monitor the study

Changes in addresses
Example: If an amendment to the protocol changes the study schedule in scope or activity, or changes the
potential risk to the participant, the informed consent document must be revised or amended with clear
reference to the original document, submitted to the IEC for review and approved by the IEC before use. The
revised or amended informed consent document must be used to obtain re-consent from any participants
currently enrolled in the study if the participant is affected by the amendment, and must be used to document
consent from any new participant enrolled after the approval date of the amendment.
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3. BACKGROUND AND RATIONALE
(ICH 6.2; AGEK 3; SPIRIT #6)
Any statements that rely on existing knowledge or published information shall be adequately referenced.
Describe disease of interest
EXAMPLE: INIS trial
Background
Neonatal sepsis is a major cause of mortality and morbidity and has been implicated in the
causation of perinatal brain damage and cerebral palsy, both in term and preterm infants1 2.
Although antibiotics are the mainstay of therapy, increasing numbers of bacteria are resistant to
them3 4. Effective adjunctive strategies are therefore needed.
Incidence, potential impact on mortality and problems in diagnosis
In a prospective study in seven Australian neonatal intensive care units (NICUs), Isaacs and
colleagues reported an annual incidence of sepsis of 6.6 per 1000 live births, of which 75% were
late onset (more than 48 hours after birth). Overall hospital mortality for sepsis was 10%5. In a
cohort of 54 UK neonatal units in 1998 (www.child-health.dundee.ac.uk/research/ukneonatalstaffing/)6, 204 (5%) of 3,963 consecutive admissions to neonatal units had a positive blood
culture. Of these, 16 (8%) died. Of 3,759 (95%) babies with negative blood cultures, 95 babies
died (2.5%). For very low birthweight (VLBW) infants with positive blood cultures, mortality was
14% (see table 1, p 10). In a recent North American cohort, mortality in VLBW infants with
septicaemia was 21%7. However, these figures may underestimate the true incidence of
neonatal sepsis. Blood cultures may often be negative if less than 1 ml of blood is sampled8.
Furthermore, while sepsis was the primary cause of death in most infants under 1000g at
autopsy, it was clinically undiagnosed in 61% of cases 9. Sepsis-specific mortality rates should
therefore be interpreted with caution, as the diagnosis may often be inaccurate. More reliable
evidence would be provided by randomised comparisons of the effects of specific interventions
on mortality from all causes.
Potential impact of sepsis on the perinatal brain
Recent evidence suggests that sepsis is also important in the pathogenesis of neurodevelopmental impairment of perinatal origin. In a case-control study of 424 births, Grether and
Nelson found that infants exposed in utero to maternal infection at term were 9 times more likely
to have cerebral palsy than controls1. In another case-control study of 96 term infants, levels of
cytokines in neonatal blood spots were consistently higher in children diagnosed with cerebral
palsy at 3 years of age than in controls, suggesting that an inflammatory response may be
important in the aetiology of cerebral impairment10. In preterm infants, sepsis is also associated
with subsequent adverse neuro-developmental outcome2. Dammann and Leviton have
suggested that infection remote from.
3.1
Background and Rationale
(ICH/E6 6.2; AGEK 3.1; SPIRIT #6)
Describe the research question, including summary of relevant studies (published and unpublished) examining
benefits and harms for each intervention; including disease background, e.g. epidemiology, current standard
of care (if relevant) and also establish its context by giving a clear statement on the primary and secondary
purposes of the study.
Briefly describe other relevant studies currently enrolling patients identified at clinicaltrials.gov or other study
registers and the difference to the proposed trial.
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EXAMPLE
Other relevant studies
The International Clinical Trials Registry Platform (ICTRP) was last searched on May 4th, 2009
using the following search terms: 'osteoarthritis' (in Condition) AND 'glucosamine' (in
Intervention) AND 'recruiting' (in Recruitment status). The search identified no ongoing placebo
controlled trials.
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3.2
Investigational Product (treatment, device) and Indication
(ICH/E6 6.2.1; AGEK 2; SPIRIT #6)
ICH: Name and description of the investigational product(s).
This section should contain a description of the investigational product, its class, make-up, chemical properties
and any relevant physical properties including any available pharmacologic data (the Investigator’s Brochure
or the summary of product characteristics, as applicable, should be referred to but not reiterated)
Medical Device (MD): brand name, manufacturer, name or number of the model/type, incl. software version
and accessories if any, to permit full identification. Populations and indications for which investigational device
is intended. Differences to authorisation (if any) / if applicable, mention CE Declaration of Conformity including
the intended purpose defined in the instruction manual. Include description of device materials in contact with
body tissues and/or fluids, summary of necessary training and experience to use device and medical and/or
surgical procedures involved in the use of the device (ISO 14155 Annex A).
Example: Patients are expected to begin treatment at the day of randomization. Study treatment must be
administered in a hospital setting. Outpatient treatment is allowed but depends on the investigator's judgment.
3.3
Preclinical Evidence
(ICH/E6 6.2.2; SPIRIT #6a)
ICH: A summary of findings from nonclinical studies that potentially have clinical significance …..
Summarise, if applicable, the available non-clinical data (published or available unpublished data) that could
have clinical relevance and justify its use in humans.
Medical devices: only applicable if needed for pre-marketed / marketed devices needing Swissmedic
notification (Guidance on the biological evaluation of medical devices is given in ISO 10993).
Briefly describe other relevant studies currently enrolling patients identified at clinicaltrials.gov or other study
registers and the difference to the proposed trial.
One may refer to the Investigator’s Brochure (IB), Investigational Medicinal Product Dossier (IMPD), Summary
of Product Characteristics (SPC) or a similar document (if applicable), by mentioning the relevant pages in that
document. Be sure that the information is up to date and references to peer reviewed papers in
(biomedical/scientific) journals should be given where appropriate.
3.4
Clinical Evidence to Date
(ICH/E6 6.2.2; SPIRIT #6a)
ICH: A summary of findings from … and from clinical trials that are relevant to the trial.
Summarise the available clinical study data with relevance to the protocol under construction (published or
available unpublished data that should be based on or referred to a systematic review). This shall include an
analysis of adverse (device) effects and any history of modification or recall. If none is available, include a
statement that there is no available clinical research data to date on the investigational product.
Medical Devices: include postmarket experience if applicable
Describe how you searched for systematic reviews or primary studies
Describe results of any systematic reviews or the systematic literature search
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EXAMPLE: MAGPIE trial
Systematic review of anticonvulsants for women with pre-eclampsia
A recent systematic review of randomised trials demonstrates that, currently, there is insufficient
evidence to either support or refute the use of prophylactic anticonvulsants13. Twelve trials have
evaluated anticonvulsants for women with pre-eclampsia. Two small studies were excluded from
the review because either no clinical outcomes were reported, or they were not reported
separately for pre-eclampsia and eclampsia14,15. Two trials have compared magnesium sulphate
with no anticonvulsant16,17 (228 women, South Africa; 64 women, Taiwan) and two have
compared magnesium sulphate with placebo18,19 (822 women, South Africa; 135 women, USA).
One quasi-randomised study (59 women, Tanzania)20 compared oral diazepam with no
anticonvulsant. The remaining trials compared magnesium sulphate with diazepam21,22 (38
women, Mexico; 28 women, Malaysia) or with phenytoin12,23,24 (2138 women, USA; 115 women,
USA; 54 women, USA).
Results
Overall, the methodological quality of these trials was average to poor. In most, concealment of
the allocation at trial entry was inadequate, and two studies excluded from their analyses >10%
of women randomised18,23. In the comparison of magnesium sulphate with no
anticonvulsant/placebo, three women allocated magnesium sulphate had a fit, compared to 13
amongst those allocated no anticonvulsant/placebo (Relative Risk 0.33; 95% CI 0.11-1.02).
There was also a non-significant trend towards a small increase in the risk of Caesarean section
for women allocated magnesium sulphate (RR 1.04; CI 0.92-1.17). There is little information
about possible effects on other important outcomes. In the comparison of magnesium sulphate
with phenytoin, women allocated magnesium were less likely to develop eclampsia (RR 0.09; CI
0.01-0.72), but more likely to have a Caesarean section (RR 1.21; CI 1.05-1.41). There were no
statistically significant differences in stillbirths (RR 0.62; CI 0.27-1.41) or neonatal deaths (RR
0.84; CI 0.41-1.74) amongst the babies allocated magnesium sulphate rather than phenytoin in
utero. There is little information about other relevant outcomes. No woman in the comparison of
magnesium sulphate with diazepam developed eclampsia. No trials have reported follow-up of
the children beyond the perinatal period, an economic evaluation, or an assessment of the costs
to the health services.
Discussion
To date, 1200 women with pre-eclampsia have been entered into trials comparing an
anticonvulsant with none. The results of these trials, when taken together, are promising in terms
of a reduction in the risk of eclampsia associated with the use of anticonvulsants. These data
should be interpreted with caution, however, as the number of events was small and the largest
study18 had a large proportion of post randomisation exclusions. Also, apart from the suggestion
of a small increase in the risk of Caesarean section associated with the use of magnesium
sulphate, there is little information about possible effects on other important outcomes, including
toxicity and side effects. Nearly 2400 women have been randomised into trials comparing
different anticonvulsants, most of whom were in one study comparing magnesium sulphate with
phenytoin12. Women allocated magnesium sulphate were less likely to fit than those allocated
phenytoin but this study provides no insight into whether giving magnesium sulphate is
preferable to withholding it. Also, the number of events was small (0 versus 10) and, apart from
an increase in the risk of Caesarean section, there are few data on other measures of maternal
morbidity. Finally, 1% of the women allocated phenytoin developed eclampsia. This is an
unusually high incidence for the reported severity of disease (only 18% had ³2+ proteinuria and
4% had been given an antihypertensive) and may, at least in part, be due to chance.
In conclusion this review, combined with evidence that magnesium sulphate is the drug of choice
for women with eclampsia25, supports magnesium sulphate as the best choice of anticonvulsant
to evaluate for women with pre-eclampsia. There is a suggestion that magnesium sulphate may
be associated with an increase in the risk of Caesarean section, which may be a tocolytic
effect26. If true, this tocolytic action might have other consequences such as an increase in length
of labour, postpartum haemorrhage and retained placenta.
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EXAMPLE: MAGPIE trial
Current use of prophylactic anticonvulsants
Internationally there is considerable variation in the use of anticonvulsants for women with preeclampsia. Amongst those who do use them, there is no consensus on either choice of agent or
which women are most likely to benefit. In the USA, for example, 99% of obstetricians use
magnesium sulphate which is given to an estimated 5% of pregnant women before delivery12. In
contrast, 23% of UK obstetricians never use any prophylactic anticonvulsants27. In the past, only
2% used magnesium sulphate, others preferring diazepam, phenytoin or chlormethiazole6,28,29.
There has recently been a substantial shift towards using magnesium sulphate in the UK, with
40% of obstetricians now reporting that they use it27.
Mode of action for magnesium sulphate
Exactly how magnesium sulphate might control eclamptic convulsions is unclear. Magnesium
may have a localised cerebral effect. For example, it may cause vasodilatation with subsequent
reduction of cerebral ischaemia15, and/or block some of the neuronal damage associated with
ischaemia30,31.
A possible mechanism for vasodilatation is relaxation of smooth muscle, and it has been
suggested that magnesium may have a generalised effect on all smooth muscle, including the
peripheral vasculature and uterus. Alternatively, any effects of magnesium sulphate in control of
eclamptic convulsions may be, wholly or partially, through its role as a blocker of N-methyl-Daspartate (NMDA) receptors in the brain. These NMDA receptors are activated in response to
asphyxia, leading to calcium influx into the neurones which causes cell injury. It is suggested that
magnesium may block these receptors, so reducing calcium influx and protecting the neurones
from damage.
Possible benefits of magnesium sulphate
Magnesium sulphate may reduce the risk of eclampsia. This effect may be reflected in a lower
risk of other complications of eclampsia, such as renal failure, cerebrovascular accident and liver
failure, as well as improved blood pressure control. If real, these potential benefits may lead to
less time spent in hospital and less use of intensive care facilities. Suggestions about the
possible mode of action for magnesium sulphate have also led to hypotheses about potential
benefits for children who are exposed while in utero. For example, if magnesium sulphate
administration does delay progression of pre-eclampsia this may be reflected in a reduction in
preterm delivery. The mechanism for such a reduction could be either later onset of spontaneous
labour or less obstetric intervention. In addition, it has been suggested that magnesium sulphate
administration may improve the outcome for asphyxiated babies 32. For preterm babies, exposure
to magnesium sulphate may also be associated with a lower risk of cerebral haemorrhage33,
which in turn could be reflected in a reduction in the risk of cerebral palsy for these low
birthweight infants34,35,36. All these hypotheses are based on observational data and, although
they are being tested in randomised trials, these data await confirmation37,38.
Possible hazards of magnesium sulphate
Potential hazards of magnesium sulphate include, for the woman, respiratory depression,
respiratory arrest and hypotension39. Cardiac arrest is a theoretical risk, but in practice is likely to
be rare as a complication of magnesium sulphate. If magnesium does relax smooth muscle it
may also have a tocolytic effect26 leading to an increase in a length of labour, postpartum
haemorrhage, retained placenta and blood transfusion. In addition, potential side effects include
nausea, vomiting, thirst, flushing of the skin, hypotension, arrythmias, drowsiness, confusion, and
muscle weakness. We therefore need reassurance that magnesium sulphate, when used for
women with pre-eclampsia, is well tolerated. Also magnesium sulphate may have an effect on
mood post partum and so it is important to check whether it has any influence on the incidence of
postpartum depression. For the baby, possible hazards related to hypermagnesaemia are similar
to the mother and include respiratory depression, hypotonia and hypotension32,40. Recently it has
been suggested that in utero exposure to magnesium sulphate for prevention of preterm delivery
may increase the risk of mortality for the baby41, when compared to other tocolytic agents.
However there are several other possible explanations for these data, as the number of events
was very small and there were imbalances between the treatment groups37,38. Also, the dose of
magnesium sulphate was very high (median 49.5g). Whatever the effects of magnesium sulphate
on the outcome for low birthweight children, reassurance will still be required about possible
effects for bigger babies, as the pathophysiology of cerebral palsy in these two groups is very
different36.
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3.5
Dose Rationale / Medical Device: Rationale for the intended purpose in
study (pre-market MD)
(ICH/E6 6.2.4; SPIRIT #6a)
ICH: Description of and justification for the route of administration, dosage, dosage regimen, and
treatment period(s).
Provide the rationale used for selection of the dose, route, regimen and dosage period or the intended
purpose in the study (medical devices: the application etc)
3.6
Explanation for choice of comparator (or placebo)
(AGEK 11.3; SPIRIT #6b)
Explain the rationale for the comparator chosen for the study (include an explanation whether placebo is
ethically justified or alternatively the comparator proved to be another effective treatment to compare with the
investigational product)
3.7
Risks / Benefits
(ClinO, Appendix 4, 3.5; Art 25d2; ICH/E6 6.2.3; AGEK 11.1; SPIRIT #6a; MD: ISO 14155 Annex A & ISO
14971)
ICH: Summary of the known and potential risks and benefits, if any, to human subjects.
Provide a discussion of the known and potential risks and benefits to human, include a description of possible
or anticipated adverse effects and a discussion of measures to control or mitigate the risks (if available
reference to the risk analysis report should be made) and how post-trial care is organised. For studies without
immediate benefit to the study participants, a rationale should be provided stating how the results of the study
could be beneficial for future participants due to e.g. a better understanding of the disease, mechanism of
action etc.
Describe, if applicable and relevant, the potential threats to the study, e.g. competing trials, and
anticipate risk minimisation.
For medical devices a device risk analysis and risk assessment should be included according to EN ISO
14971. This shall describe the anticipated adverse device effects, residual risks associated with the
investigational device and the procedures involved in its use. Risks associated with participation in the clinical
investigation shall be described and possible interactions with concurrent medical interventions shall be listed.
A statement of the anticipated clinical benefit shall be given and a risk to benefit rationale. This shall include
an analysis of adverse device effects and any history of modification or recall in relation to safety and clinical
performance in relation to both the device under investigation and the comparator(s).
Summarize the need for the study. The rationale should include the perceived benefits of any intervention
which is to be evaluated. It should outline how the intervention under investigation might work, especially if
there is little or no previous experience. Also provide justification for placebo-control if applicable.
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EXAMPLE: MAGPIE trial
Why is a trial needed now?
In 1995, magnesium sulphate was shown to be the anticonvulsant of choice for women with
eclampsia (see table). These results had a major impact on both practice and policy throughout
the world. Magnesium sulphate for the treatment of eclampsia is now included in the essential
drugs list of the World Health Organisation and is recommended in the practice guideline
produced by the Royal College of Obstetricians and Gynaecologists, London.
Table: Data from the Collaborative Eclampsia Trial on maternal deaths and recurrence of
convulsions
*RR = relative risk; CI = confidence interval; * outcome not known for 1 woman
Having switched to magnesium sulphate for women with eclampsia, many clinicians are also
reviewing their policies for anticonvulsant prophylaxis. As discussed above further evidence is
required to help them decide whether its use would be beneficial and, if so, for
whom. Nevertheless many clinicians have begun using magnesium sulphate for women with
preeclampsia, and others are considering starting to use it. There is currently a window of
opportunity for properly evaluating this use of magnesium sulphate. Results of the Magpie Trial
will provide a reliable basis for decision-making about the care of women with preeclampsia.
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EXAMPLE: PVAG-14 pilot trial
III. RATIONALE OF THE STUDY
Although huge progress has been achieved in the treatment of patients with Hodgkin's lymphoma
in the last decades, the prognosis of patients with intermediate-stage disease is still
unsatisfactory. Unlike the progress in patients with early- and advanced-stage disease, the
standard regimen ABVD for these patients has remained unchanged for many years. Therefore,
clinical trials are warranted to further improve the treatment of these patients incorporating new
and possibly more effective agents.
A new regimen derived from the ABVD-regimen was developed for this study (PVAG-14). No
prospective trial has been published about the proposed chemotherapy regimen so far but
preliminary data from an ongoing phase I/II trial showed promising results with favorable safety
profile in a three-weekly schedule (I.2.2, p. 21). Given the experience of earlier trials with
gemcitabine-combinations (I.2.2, p. 21) the proposed approach seems promising and feasible.
Radiation will be administered after chemotherapy at a dose of 30 Gy of IF-RT since no definitive
results are available from the HD11 yet justifying a lower radiation dose.
No phase I dose-finding trial has been conducted to determine the optimal dose of gemcitabine
administered concomitantly with doxorubicin, vinblastine, and prednisone in a bi-weekly regimen.
According to pharmacokinetic studies a weekly dose of at least 350 mg/m² is required for optimal
tumor control. Given the extensive data of clinical trials with gemcitabine (either administered as
single-agent or in combinations) a dose of 1000 mg/m² (corresponding to a dose intensity of 500
mg/m²/week) seems to be most promising. However, the dose of doxorubicin in the ABVDregimen has not been challenged since its introduction in the 1970's. Recent trials in nonHodgkin lymphoma indicate that higher dose-intensities may be more effective than standard
dosing regimens for the treatment of lymphoma. Doxorubicin doses of 50 mg/m² seem to be too
high to be given in combination with other myelosuppressive agents like gemcitabine and
vinblastine. Given the dose-intensities administered in trials of gemcitabine and doxorubicin
combinations the most promising doses seem to be 25 mg/m² and 35 mg/m². Since complete
response rate with ABVD is more than 90% in this population, a phase I dose-escalation study
was deemed unfeasible by the trial steering committee. Therefore, a randomized phase II trial is
the appropriate design to evaluate the activity and optimal dose level of this new regimen.
FDG-PET performed early during treatment (e.g., after two cycles of chemotherapy) may be a
promising approach for response-adapted treatment strategies. However, no data are available
from prospective studies of patients with HD treated with a uniform regimen regarding its
predictive value – a prerequisite to develop such strategies. Therefore, assessment of the
predictive power of early FDG-PET will be another objective of the trial. Since assessment and
quantification of predictive value is limited if the results of early FDG-PET evaluations guide
subsequent treatment of patients no consequences regarding treatment will be drawn in this trial.
Describe whether any procedures are in place to inform participants about the results of the trial.
Describe whether and how participants are allowed to be informed about the intervention received during the
trial in case of a blinded trial.
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Access to effective trial interventions
3.8
Justification of choice of study population
(ClinO, Art 25d4, Art. 15-17; ICH/E6 6.2.6; AGEK 11.2)
ICH: Description of the population to be studied.
Describe the choice of the study population and the rationale for it (mandatory in case of vulnerable
participants)
For vulnerable participants (e.g. minors, participants incapable of judgment or participants under tutelage), the
following issues need to be addressed in the protocol
-
Rationale for the inclusion of vulnerable participants (i.e. reasons why comparable results / findings
cannot be obtained from adults or those capable of judgment)
-
Describe how the legal representative is informed regarding the procedures of the study and how his
or her consent is obtained.
-
In the event that the minor and / or participant under tutelage is capable of judgment, describe how
their assent is collected in addition to the consent of their legal representative
-
In the event of a participant incapable of judgment, mention that signs and symptoms showing that
the participant is unwilling to participate in the study will result in the participant being excluded from
participation.
For emergency situations, the following aspects should be described:
-
How to obtain, without unjustified delay, an informed consent by the legal representative of
participants that are incapable of judgement, minors or under tutelage
-
How the will of the participant can be elucidated later (when the participant is capable of judgment) or
with the help of accessible relatives
-
Mention that signs and symptoms showing that the participant is unwilling to participate in the study
will result in the participant being excluded from participation.
-
The guarantee that a physician not participating in the study, safeguards participant interest and
insures proper medical care
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4. STUDY OBJECTIVES
(ICH/E6 6.3; AGEK 3; SPIRIT #7)
ICH: A detailed description of the objectives and the purpose of the trial.
Describe the overall, primary and secondary objective(s) of the study in a clear and simple form. The primary
objective should be clearly marked as such.
4.1
Overall Objective
Provide a clear, simple statement describing the overall purpose(s) of the study, explaining why the study is
performed. (e.g., The purpose of this study is to evaluate whether Test Drug A lowers blood pressure with a
similar efficacy as known for Comparator Drug B in participants with moderate to severe hypertension; The
study aims to describe an efficacy and safety profile for Test Drug A compared to Drug B for the treatment of
moderate to severe hypertension).
Describe the aims of the trial. This does not necessarily require exact descriptions of the outcomes (i.e.
definitions) but the concept of the outcome measures (e.g. activity, effectiveness, safety). When stating the
aims of a trial, consider using the PICO (Population, Intervention, Control, Outcome) approach. Note that
exact definition of outcomes should be described in Error! Reference source not found.. Think about
classifying the trial according to ICH Harmonized Tripartite Guideline E8 as human pharmacology, therapeutic
exploratory, therapeutic confirmatory, or therapeutic use trial.
EXAMPLE: SYTRUST trial
Overall Goal
To determine the feasibility, accuracy, cost-effectiveness and impact on pregnancy outcome of
on-site syphilis testing and related health promotion strategies in the community antenatal clinics
of a rural South African health district.
Specific Objectives
1. Through a pre-intervention phase, to document the current strategies for screening and
treating maternal syphilis and other STDs in the antenatal clinics, and to determine their
effectiveness.
2. To gain an understanding of women’s health seeking behaviours during pregnancy through
an assessment of 1) awareness and understanding of syphilis and other STDs and their impact
on pregnancy, and 2) reasons why women often book late for antenatal care, or do not book at
all.
3. To implement in six intervention clinics, on-site syphilis testing and health promotion
strategies aimed at 1) increasing awareness of the impact of STDs, particularly syphilis, on
pregnancy, 2) reducing the gestational age that women book for antenatal care, 3) increasing the
number of women that book for antenatal care, 4) increasing the proportion of infected women
who complete a course of treatment for syphilis.
4. To develop effective partner notification strategies within the context of antenatal care.
5. To evaluate the feasibility, accuracy, and cost-effectiveness of this strategy.
6. To implement the strategy in control clinics if the findings are positive.
7. To disseminate this data and thereby inform reproductive health policy and practice, and
hence improve reproductive health status.
4.2
Primary Objective
Provide a clear, simple statement describing the primary objective of the study (e.g., The study seeks primarily
to determine the effect of Test Drug/Device A on diastolic blood pressure compared to Drug/Device B)
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4.3
Secondary Objectives
Provide a clear, simple statement describing the secondary objectives of the study (e.g., Secondary objectives
are to assess efficacy of Test Drug A on systolic blood pressure compared to Drug B).
4.4
Safety Objectives
In studies with efficacy as primary and secondary endpoints safety is always an additional objective.
Provide a clear, simple statement describing the safety endpoints of the study. (e.g., the study aims to assess
long-term safety of Drug/Device A and its tolerability in terms of incidence of gastrointestinal side effects and
use of rescue medication).
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5. STUDY OUTCOMES
(ICH/E6 6.4.1; AGEK 4.1; SPIRIT #12)
ICH: A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured
during the trial.
Describe the primary, secondary, and other outcomes, including the specific measurement variable (e.g.,
systolic blood pressure or description of surrogate marker for non-measurable variables), analysis metric (e.g.,
change from baseline, final value, time to event), time point for each outcome etc. Explanation of the clinical
relevance of chosen efficacy and harm outcomes is strongly recommended.
Describe exact definitions for each outcome: what (method) is assessed by whom (independent
adjudication?), at which timepoint under which conditions (blinded?). The following components need to be
described explicitly (for each outcome if different): 1) domain (e.g. pain, quality of life etc.); 2) specific
measure/instrument (e.g. "Hamilton Anxiety Rating Scale", "blood pressure measured in sitting position on
both upper arms after resting for 5 minutes using a sphygmomanometer", etc.); 3) metric i.e. the analytic
approach (e.g. risk ratio, difference in absolute values, repeated-measures using all follow-up values, etc.); 4)
cut-off for continuous/quantitative measures if used; 5) time frame i.e. the follow-up visit from which the
outcome will derived (e.g. 2 years after randomization); 6) outcome assessor (e.g. patient, blinded and
independent adjudication committee).
5.1
Primary Outcome
The primary outcome (or endpoint) is the main result that is measured at a precise time-point or at end of
treatment/intervention to verify whether a given treatment was successful or not.
Provide a short description of the primary outcome variable (usually only one and with regard to efficacy) and
the rationale for the choice of outcome. (Safety can also be a primary endpoint in a safety trial. e.g., The
primary endpoint will be the change of diastolic blood pressure from baseline to Day 21.)
Description as detailed above for all primary outcomes (usually one but not more than three as a rough
guidance). The primary outcome(s) should be the most relevant one(s) regarding the objective of the trial i.e.
for phase III trials the most clinically relevant efficacy outcomes, for phase II trials activity outcomes or safety
outcomes to determine dosing, for phase I trials pharmacokinetic/-dynamic or tolerability outcomes, and for
phase 0/proof-of-concept trials pharmacodynamics or activity outcomes.
EXAMPLE
11.1.1. Hematological toxicity
Toxicity will be assessed according to NCI Common Terminology Criteria version 3.0 (CTCAE)
published June 10, 2003 (see Study Manual).
The primary toxicity outcome is defined as the percentage of patients with at least one episode of
a hematological toxicity grade III/IV between treatment start until 28 days after the last study drug
administration as assessed by each investigator based on regular laboratory studies as defined
in chapter 10. For the purpose of this study an episode of a hematological toxicity grade III/IV is
defined as one or more laboratory studies with:
•
Neutrophils < 1000/μL or
•
Leukocytes < 2000/μL or
•
Platelets < 50,000/μL or
•
Hemoglobin < 8.0 g/dl
An episode ends if all hematological parameter(s) return to at least toxicity grade II.
5.2
Secondary Outcomes
Provide a short description of the secondary outcome variables and the rationale for the choice of outcomes.
(e.g., Secondary endpoints will be the change of diastolic blood pressure from baseline to Day 10, to Day 60,
change of systolic blood pressure from baseline to Day 10, Day 21, Day 60.)
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Ditto (approximately four other (clinically) relevant outcomes addressing the objective).
5.3
Other Outcomes of Interest
Provide a short description of other outcome variables of interest and the rationale for the choice of endpoints.
Ditto. Any other outcomes of interest e.g. to disentangle how interventions might work (different survival
outcomes, components of composite event outcomes, subscales. Exploratory outcomes, or outcomes with
unclear validity.
5.4
Safety Outcomes
Provide a short description of the safety outcome variables referring to e.g. specific adverse events, rate of
adverse events in general, laboratory parameters and/or vital signs (e.g., Incidence and severity of
gastrointestinal side effects related to study drug intake during the whole study.)
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6. STUDY DESIGN
(ICH/E6 6.4; AGEK 4; SPIRIT #8)
6.1
General study design and justification of design
(ICH/E6 6.4.2, 6.4.5; AGEK 4.2; SPIRIT #8)
ICH: The scientific integrity of the trial and the credibility of the data from the trial depend substantially
on the trial design.
ICH: A description of the type/design of trial to be conducted (e.g., double-blind, placebo-controlled,
parallel design) and a schematic diagram of trial design, procedures and stages.
ICH: The expected duration of subject participation, and a description of the sequence and duration of
all trial periods, including follow-up, if any.
Describe the design of the study and its rationale, the type (e.g., placebo-controlled, parallel design, who is
blinded), allocation ratio and framework (eg, superiority, equivalence, non-inferiority, exploratory). Provide a
description of intended procedures and stages, the expected duration of participant’s participation, description
of sequence and durations of all trial periods, incl. Follow-up. Provide a discussion of the known or potential
problems and limitations of the design.
The following information should be included in this section:
-
treatments/intervention to be studied (drugs/medical device, doses and procedures)
-
population to be studied and the number of participants to be included (if known or applicable)
-
level and method of blinding/masking (e.g. open, blinded evaluators and unblinded participants
and/or investigators).
-
kind of comparator(s), (e.g. placebo, no treatment, active drug, dose-response, historical and study
configuration (parallel, cross-over)
-
method of assignment to treatment/intervention (randomisation, stratification)
-
sequence and duration of all study periods
Use "labels" (no details) to provide an overall picture of the study
EXAMPLE: ASCEND trial
Design
ASCEND is a mail-based, multi-centre, randomised controlled trial which aims to demonstrate
whether aspirin and/or omega-3 fatty acids reduce the risk of cardiovascular events in individuals
with diabetes who do not already have diagnosed occlusive arterial disease, and whether such
benefits outweigh any potential risks.
In order to do this reliably, at least 10,000 patients with diabetes and no clinical evidence of
occlusive arterial disease will be randomly allocated to receive 100mg aspirin daily or matching
placebo tablets and 1g omega-3 fatty acid or matching placebo capsules for about 5 years. A
study of this size should have excellent power to detect a 20% proportional reduction in the
cardiovascular event rate among such patients. In order to be cost-effective, this study is being
undertaken predominantly by mail, with back-up from a 24-hour Freefone Service.
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Study flow diagram
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6.2
Methods of minimising bias
(ICH/E6 6.4.3; AGEK 4.3; SPIRIT #16, 17)
ICH: A description of the measures taken to minimize/avoid bias, including: Randomization, Blinding.
Describe measures to be taken in order to minimise or avoid bias; if applicable describe randomisation,
blinding and other measures in the subsections below
6.2.1
Randomisation
Describe the exact randomisation method (unit, what, allocation ratio, number generation mechanisms, block
randomisation, stratification, who generates and concealment of list)
Describe the exact randomization method. The following elements need to be included:

The unit of randomization; usually patients but sometimes body parts or clusters (hospital wards,
physicians) are randomized

What is randomized i.e. the interventions

Allocation ratio

Mechanism of how random numbers are generated

Blocking: whether simple randomization or randomization in blocks is planned. For block
randomization, block size(s) and the mechanism of variation need to be specified

Stratification: whether or not randomization is stratified. For stratified randomization, all stratification
variables need to be specified

Who is responsible for generating and implementing the randomization list

A statement that randomization list(s) is concealed from any study personnel involved in patient
recruitment
EXAMPLE: Randomization SOP CTU Bern
Randomization
After patient registration in the web-based data entry system and confirmation of all inclusion and
exclusion criteria patients are randomized using the same system thus ensuring concealment of
allocation (central web-based randomization). Patients are randomized in a 1:1 ratio to one of the
two intervention groups: Intervention 1, intervention 2. The allocation sequence is generated by
an independent statistician at CTU Bern not involved in the final analysis of the trial. It is based
on computer generated random numbers in randomly varying blocks of 4, 6, and 8 using the
statistical software package Stata (StataCorp LP, College Station, TX, USA). Randomization is
stratified by the following factors: study center, age (<60years vs. >/= 60 years). Correct
implementation of the randomization list in the web-based system is quality controlled by the
responsible statistician. The randomization list is kept electronically at CTU Bern in a password
protected file. Study personnel involved in patient recruitment will have no access to the list. The
statistician responsible for the final analysis will also have no access to the list until the primary
analysis of the trial is finished.
6.2.2
Blinding procedures
Describe how blinding is ensured, and who will be blinded after assignment to interventions (e.g., trial
participants, care providers, outcome assessors, data analysts)
Describe how blinding is ensured i.e. production and packaging.
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6.2.3
Other methods of minimising bias
Describe other methods if applicable (e.g., the use of validated questionnaires)
6.3
Unblinding Procedures (Code break)
(ICH/E6 6.4.8; AGEK 4.2; SPIRIT #17b)
ICH: Maintenance of trial treatment randomization codes and procedures for breaking codes.
If blinded, describe circumstances under which unblinding is permissible and procedures for revealing a
participant’s allocated intervention will be allowed during the trial, e.g. codes in sealed envelopes, list persons
having access to envelopes, also in case of suspension or premature study termination.
Describe unblinding procedures if applicable. Refer to a SOP if appropriate.
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EXAMPLE: HWI trial
9.6 Unblinding
In general, breaking the statistical blind should be considered only when knowledge of the
treatment assignment is deemed essential for the study patient's care by the participant's
physician or a regulatory body. Unblinding should be restricted to emergency situations and is
expected to be extremely rare in this trial. It may be required in the following circumstances:
- Occurrence of a serious adverse event where the event appears possibly related to one of the
interventions and the event is not listed in one of the package inserts i.e. the serious adverse
event is considered to be a potential suspected unexpected serious adverse drug reaction
(SUSAR) and would require expedited reporting.
- Occurrence of a severe allergic reaction and knowledge of the treatment assignment is deemed
essential for the participant's care.
- Use of the investigational medicinal product by someone not participating in the clinical trial e.g.
if a child in the household of a participant accidentially takes a study medication.
- Knowledge of the treatment assignment is deemed essential for the participant's care for any
reason.
Code breaks/emergency envelopes will be held in the pharmacy. The on-call pharmacist at the
Institute for Hospital Pharmacy of the Inselspital Bern will be available to perform the code break
at any time (contact by the central number of the Inselspital Bern, 031 632 21 11).
Only healthcare professionals involved in the care of the relevant study patient can require
unblinding. The healthcare professional should immediately contact the Institute for Hospital
Pharmacy and request code breaking by giving specific reasons. The responsible pharmacist will
provide the information as required. On receipt of the relevant information, the treating healthcare
professional should attend to the participant's medical emergency. Where possible, it is important
that all other members of the study team e.g. other investigators, statisticians etc. remain blinded.
The responsible pharmacist of the Institute for Hospital Pharmacy will inform the principal
investigator of any request for unblinding and the reasons for the request. The investigator
responsible for the care of the study patient will record the unblinding and reasons in the medical
chart and in the eCRF. The responsible pharmacist will also record any unblinding and the
reasons in the code list.
Any unblinding will be documented in the study report.
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7. STUDY POPULATION
(ICH/E6 6.2.6, 6.4.6; AGEK 3.2, 5; SPIRIT #9, 10, 15, 16, 21)
ICH: Description of the population to be studied.
Describe in the subchapters below the population to be studied; this should include a description of the study
settings if relevant (e.g., out-patients, community clinic, academic hospital) and list of centres/countries where
data will be collected (or reference to where list of study sites can be obtained). Provide plan of actions to be
taken if the enrolment goals are not met.
7.1
Eligibility criteria
(ClinO, Art 25d5; ICH/E6 6.5.1&6.5.2; AGEK 5.2&5.3; SPIRIT #10)
ICH: Subject inclusion and exclusion criteria.
Describe in detail the inclusion and exclusion criteria for the participants’ eligibility to the study (if applicable,
eligibility criteria for study centres and individuals who will perform the interventions (e.g., surgeons,
psychotherapists)). Create a list of criteria and be as specific as possible.
Participants fulfilling all of the following inclusion criteria are eligible for the study, for example:
-
Informed Consent as documented by signature (Appendix Informed Consent Form)
Etc. continue as applicable for this study
The presence of any one of the following exclusion criteria will lead to exclusion of the participant,
for example:












Contraindications to the class of drugs under study, e.g. known hypersensitivity or allergy to
class of drugs or the investigational product,
Define drugs not allowed during the study or for specific periods of time prior to the
administration of the test dose,
Women who are pregnant or breast feeding,
Intention to become pregnant during the course of the study,
Lack of safe contraception, defined as: Female participants of childbearing potential, not using
and not willing to continue using a medically reliable method of contraception for the entire
study duration, such as oral, injectable, or implantable contraceptives, or intrauterine
contraceptive devices, or who are not using any other method considered sufficiently reliable
by the investigator in individual cases.
Please note that female participants who are surgically sterilised / hysterectomised or postmenopausal for longer than 2 years are not considered as being of child bearing potential.
Other clinically significant concomitant disease states (e.g., renal failure, hepatic dysfunction,
cardiovascular disease, etc.),
Known or suspected non-compliance, drug or alcohol abuse,
Inability to follow the procedures of the study, e.g. due to language problems, psychological
disorders, dementia, etc. of the participant,
Participation in another study with investigational drug within the 30 days preceding and during
the present study,
Previous enrolment into the current study,
Enrolment of the investigator, his/her family members, employees and other dependent
persons,

Specific exclusions for the disease under study,

Specific concomitant therapy washout requirements prior to and/or during study participation,

Dietary restrictions,

Etc. continue as applicable for this study.

Patients with main diagnoses will be included in this study.

Patients must meet all of the inclusion criteria and none of the exclusion criteria to be enrolled in the study.

No study-specific procedures (i.e., assessments/treatments not required in clinical practice) may be
performed until an eligible patient has signed an approved informed consent to participate in the study.
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
List criteria that describe the overall nature of the population of interest

Signed informed consent with understanding of the study procedures and the investigational nature of the
study
EXAMPLE: RECORD trial
2.1 Who will be considered for trial entry?
The trial will involve people aged 70 or over who have had a previous fracture:
I.
Those who have sustained a fracture (except cervical spine, skull or face) in a fall from no
more than a standing height within the previous two years (while eligible patients may have
sustained more than one fracture, those who have high energy transfer injury will not be
eligible)
II.
Those with a clinical vertebral fracture (defined as a definite clinical event with radiological
evidence* of an incident vertebral fracture)
Potential participants will be identified by study nurses based in each clinical centre from
amongst patients attending hospital as outpatients or inpatients. A log will be kept of patients
meeting these criteria, describing the reasons if they are not subsequently recruited to the trial.
(Depending on the numbers of people attending hospital who are recruited, additional patients
may also be identified from medical records as having sustained an eligible fracture in the
preceding two years.)
EXAMPLE: PVAG-14 pilot trial
Inclusion criteria
-
Age: 18-60 years
-
Histologically confirmed diagnosis of Hodgkin's lymphoma
-
Clinical Stage IA, IB, IIA with at least one of the riskfactors a-d given below
-
Clinical Stage IIB with one or both riskfactors c-d given below
Riskfactors:
a) Large mediastinal mass (≥ 1/3 of the greatest thorax diameter as measured by chest x-ray)
b) Extranodal involvement
c) High erythrocyte sedimentation rate (≥ 50 mm/h in patients without B-symptoms, ≥ 30 mm
inpatients with B-symptoms)
d) Three or more involved lymph node areas
-
No prior therapy for Hodgkin's lymphoma (exception: pre-phase treatment with corticosteroids
and vinca-alkaloids for a maximum of seven days may not preclude trial participation if
clinically indicated and all staging examinations have been performed; all forms of prior
radiotherapy preclude trial participation)
-
Life expectancy > 3 months according to investigator judgement.
-
Signed informed consent with understanding of the study procedures and the investigational
nature of the study.
-
Patient agrees that personal data and tissue samples are provided to the GHSG

List criteria that exclude patients from the study although inclusion criteria are met e.g. specific
laboratory values

Pregnant or nursing women

Known intolerance to any protocol intervention

Participation in another clinical trial
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
7.2
Patient's lack of accountability, inability to appreciate the nature, meaning and consequences of the
study and to formulate his/her own wishes correspondingly
Recruitment and screening
(ClinO, Art 25, Appendix 3, 1.4 & 1.6; AGEK 5.1; SPIRIT #15)
Describe how, where and by whom participants are recruited / preselected for study, also mention in case of
advertisement; describe any screening requirements (e.g. laboratory or diagnostic tests). Refer to section 9.4.
for description of screening procedures. Describe any payment or compensation given to study participants.
Describe the process of recruitment (for example advertisements with place(s) of publication, consecutive
patients with no selective recuitment) and enrolment.
See section Error! Reference source not found., p. Error! Bookmark not defined. for a description of
required pre-study assessments. Note that assessments done before study inclusion are only allowed if part of
routine clinical practice. These assessments are done to establish eligibility of patients. Study-specific
procedures must only be done after study inclusion i.e. after the informed consent form was signed. Pre-study
assessments should be performed within 28 days prior to registration.
7.3
Assignment to study groups
(AGEK 5; SPIRIT #16)
Describe how participants are randomised (tools, by whom, when) and how associated treatment assignment
will be made. Mechanism of implementing the allocation sequence (eg, central telephone; sequentially
numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are
assigned.
All patients who meet the eligibility criteria for study entry can be enrolled into the study.
Eligible patients will be registered and randomized in the study centrally via the Internet:
URL: enter the URL of the study database
For randomization, the following is required:

All inclusion criteria satisfied

No exclusion criterion satisfied

Patient briefing and signed informed consent form
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EXAMPLE: CRASH trial
Randomisation
Patients eligible for inclusion should be randomised, and the study treatment started, as soon as
possible. Randomisation is done by telephoning a 24-hour toll-free service
###
and takes only about two minutes. The questions that will be asked by the telephone operator
prior to allocation of the treatment packs are shown in Appendix 2. The study computer will then
randomly assign a treatment pack number that will identify one of the CRASH treatment packs
stored in the emergency department. Once a patient has been randomised, we will definitely wish
to learn the outcome in hospital, even if the trial treatment gets interrupted or is not actually
given.
7.4
Criteria for withdrawal / discontinuation of participants
(ClinO, Art 9; ICH/E6 6.5.3; SPIRIT #21b)
Subject withdrawal criteria (i.e., terminating investigational product treatment/trial treatment) and
procedures specifying: a) When and how to withdraw subjects from the trial/ investigational product
treatment. c) Whether and how subjects are to be replaced.
Describe the criteria and procedures when and how participants are withdrawn from the study / investigational
product treatment and whether or not and how participants will be replaced. Refer to Section 9.2.5 for
description of follow-up procedures.
(e.g., withdrawal of informed consent, non-compliance, disease progression, safety, etc. or study or routine
procedure must be stopped, e.g. due to safety concerns]
Describe circumstances under which treatment should/must be stopped prematurely and subsequent
procedures.
Investigators will make every reasonable effort to keep each patient on the study until all planned treatments
and assessments have been performed. When a patient ends the treatment phase of the study prematurely,
the date and reason for early treatment discontinuation will be noted in the source document and the
appropriate portion of the CRF add additional notification if required e.g. direct information to sponsor with
timeframe. Investigators will make any reasonable effort to collect and report end-of-treatment evaluations
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The end-of-treatment evaluation should be performed before any other therapeutic intervention.
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EXAMPLE: Bortezomib in HD trial
Early withdrawal from study treatment
Protocol therapy will be discontinued at any time if any of the following situations occurs:
• The development of toxicity which, in the investigator’s judgment, precludes further therapy,
• Progressive disease,
• Intercurrent illness precluding further therapy, in the investigator’s opinion,
• Pregnancy,
• Patient refusal to continue,
• Patient lost to follow-up or non-compliance.
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8. STUDY INTERVENTION
(SPIRIT #11)
8.1
Identity of Investigational Products (treatment / medical device)
(ICH/E6 6.2.1, 6.4.2, 6.4.4; AGEK Checklist 2, item 3)
ICH: A description of the trial treatment(s) and the dosage and dosage regimen of the investigational
product(s).
Describe all trial treatments for each arm of the study.
8.1.1
Experimental Intervention (treatment / medical device)
ICH: Name and description of the investigational product(s).
Describe the investigational product, the name (generic and brand name), its source, formulation/material,
strength, colour etc. (e.g. a picture of the medical device), route and mode of administration for medication
(medical device: place of implantation) and the deviation from commercial product, if applicable.
8.1.2
Control Intervention (standard/routine/comparator treatment / medical device)
ICH: Name and description of the investigational product(s).
Describe the routine (standard) therapy, the name, its source, formulation/material, strength, colour etc. or if
applicable the comparator chosen (e.g. also placebo), route and mode of administration for medication
(medical device: place of implantation) and the deviation from commercial product, if applicable.
8.1.3
Packaging, Labelling and Supply (re-supply)
ICH: Also include a description of the dosage form, packaging, and labelling of the investigational
product(s).
Describe how the investigational/comparator product is labelled (sample label), packaged (e.g., blisters,
capsules, primary package) and how the supply is provided. If applicable describe logistics of re-supply esp.
for products with limited shelf life. (For post-market device studies labelling is not mandatory), describe
deviation from commercial products if applicable.
Provide a graph of the label for all trial interventions. According to Annex 13 of the EU Guidance "Manufacture
of investigational medicinal products" the label should include:

Name of the sponsor;

Pharmaceutical dosage form, route of administration, quantity of dosage units (and name/identifier of
the product and strength/potency in case of open trial);

The batch and/or code number to identify the contents and packaging operation;

The trial subject identification number, where applicable;

Directions for use;

Imprint "For clinical trial use only";

The name of the investigator (if not included as a code in the trial reference code);

A trial reference code allowing identification of the trial site and investigator;

The storage conditions;

The period of use (use-by date, expiry date or re-test date as applicable), in month/year);

"Keep out of reach of children" except when the product is for use only in hospital;
The outer packaging may include symbols or pictograms to clarify certain information, mentioned above and
the request “return empty packaging and unused products”.
Additional information for example any warnings and handling instructions, where applicable may be displayed
according to the order. A copy of each type of label should be kept in the batch record.
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On the immediate packaging when the outer packaging carries the particulars mentioned above (a-k), the
particulars a-f shall be given.
The label needs to be in the home language of the canton of each study site unless the intervention is applied
by the investigator directly (no information to study participants required) in which case an English label is
sufficient.
If regular market products are used an additional label with the following information is sufficient:

Name of the sponsor;

The trial subject identification number, where applicable;

Imprint "For clinical trial use only";

A trial reference code allowing identification of the trial site and investigator;
EXAMPLE: Lichen trial
Describe procedures for study product supply and retrieval of unused products (mention drug accountability
log)
8.1.4
Storage Conditions
Describe how the investigational product and those for the standard/routine/comparator therapy are stored
(e.g., temperature range, exposure to light, etc.). IMP / MD supplies must be kept in a secure, limited access
storage area under the recommended storage conditions.
(For devices already in use: "supply, "storage", "return or destruction" are according to standard procedures
and may be simply mentioned in the protocol without specific details)
Describe any storage and handling guidelines if appropriate, including keeping a temperature log.
8.2
Administration of experimental and control interventions
(ICH/E6 6.4.4)
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8.2.1
Experimental Intervention
ICH: Description of and justification of the treatment(s) to be administered, including the name(s) of all
the product(s), the dose(s), the dosing schedule(s), the route/mode(s) of administration, and the
treatment period(s), including the follow-up period(s) for subjects for each investigational product
treatment/trial treatment group/arm of the trial.
Describe the route, dose, regimen and the rationale for timing, doses of the investigational medical product(s)
or the device(s) plus a description of the study procedures, use and estimated exposure to humans. Selection
of doses in the study, selection of timing for individual participants (These could be optional sections for drug
studies to justify different dosages used and individual timing)
Medical Devices: This must include (especially for pre-market studies) a description of how device is used or
implanted, what surgical techniques are used and the necessary training and experience needed for its use
(e.g. may also be supported by pictures or sketches of the handling, application, implantation).
Describe administration of study treatment. Include details about: type of intervention, dosage, route of
administration, frequency, duration. If intervention is a drug (including placebo) or device provide details about
manufacturer, labelling etc. in chapter Error! Reference source not found..
EXAMPLE: CRASH trial
Study treatment (Table 2)
Each CRASH treatment pack contains:
•
•
•
•
•
11 x 2g vials of methylprednisolone (MP) or placebo
1 x 20mL sterile water for injection (for use with the loading dose)
1 x 100mL bag of 0.9% NaCl (for use with the loading dose)
CRASH stickers (for attaching to infusion bags and patient notes)
Patient information leaflet and Early Outcome Forms
Loading
2g MP (or matching placebo) over 1 hour in 100mL infusion:
1. Add 20mL water for injection to one 2g vial and mix well
2. Add contents of vial to the 100mL bag of 0.9% NaCl provided
3. Infuse over one hour
Daily Maintenance
1.
2.
3.
4.
5.
6.
0.4 g/hour for about 24 hours in 20 mL/hour infusion (MP or matching placebo):
Remove 100 mL from a 500 mL bag of 0.9% NaCl (to make room for the steroid)
Add 20 mL water for injection to each of five 2 g vials and mix well
Add all five (about 100 mL) to the 500 mL bag of 0.9% NaCl
Infuse at 20 mL/hour for about 24 hours
Repeat for maintenance day 2
N.B. As children under 16 are excluded, a simple fixed-dose treatment can be used. The dosing
regimen is that used in the NASCIS-2 and NASCIS-3 trials of MP in acute spinal cord injury.
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EXAMPLE: Bortezomib in HD trial
Study drug administration
Patients receive 1.3 mg of bortezomib per square meter of body-surface area (SA) twice weekly
for two weeks (day 1, 4, 8, 11) followed by one week without treatment (one cycle). The
maximum number of cycles per patient is eight (24 weeks).
Bortezomib is given as a short intravenous bolus injection (3-5 seconds).
8.2.2
Control Intervention
ICH: Description of and justification of the treatment(s) to be administered, including the name(s) of all
the product(s), the dose(s), the dosing schedule(s), the route/mode(s) of administration, and the
treatment period(s), including the follow-up period(s) for subjects for each investigational product
treatment/trial treatment group/arm of the trial.
Describe the route, dose, regimen and the rationale for timing, doses of the comparator (e.g. standard,
routine, placebo) medical product(s) or device(s) plus a description of the study procedures, use and
exposure. Selection of doses in the study, selection of timing for individual participants (These could be
optional sections for drug studies to justify different dosages used and individual timing).
Medical Devices: This must include (especially for pre-market studies) a description of how device is used or
implanted, what surgical techniques are used.
8.3
Dose / Device modifications
(SPIRIT #11b)
Describe criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug
dose change in response to harms, participant request, or improving/worsening disease)
Describe dose modification: how, under which circumstances etc.
8.4
Compliance with study intervention
(ICH/E6 6.6.3; AGEK Checklist 2, item 2; SPIRIT #11c)
ICH: Procedures for monitoring subject compliance.
Describe the strategies to improve adherence to the intervention, and any procedures for monitoring
adherence (e.g., return of unused medication, laboratory tests). Define non-compliance and how such
participants should be handled.
Describe how compliance will be ensured AND assessed e.g. pill counting.
EXAMPLE: HWI trial
Compliance
Patients will have to record their compliance in the diary. In addition patients are asked to send
back all study medications (including Monuril® 3g), which were not used, as well as empty
packages, together with the diary to the CTU Bern after the interview on day 10.
8.5
Data Collection and Follow-up for withdrawn participants
(ICH/E6 6.5.3; AGEK 9.2; SPIRIT #18b)
ICH: ………..b) The type and timing of the data to be collected for withdrawn subjects. d) The follow-up
for subjects withdrawn from investigational product treatment/trial treatment.
Describe the type and timing of data to be collected for withdrawn participants and how the follow up for
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withdrawn participants is organised
8.6
Trial specific preventive measures
(ICH/E6 6.6.2; AGEK 9; SPIRIT #11d)
ICH: Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or
during the trial.
Describe any specific preventive measures, including rescue medication for the trial participants or treatments
that are prohibited (restrictions), (e.g., contraception, pregnancy test, dietary requirements / omissions,
concomitant medication etc.) Their use should be recorded in the CRF. Describe their potential impact on
study objectives.
8.7
Concomitant Interventions (treatments)
(ICH/E6 6.6.2; AGEK 9; SPIRIT #11d)
ICH: Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or
during the trial.
Describe any specific or relevant concomitant care and interventions that are permitted (additional treatments)
during the trial. Their use should be recorded in the CRF. Describe their potential impact on study objectives.
Describe concomitant interventions received by all patients in the study. If there is no regulation/restriction on
concomitant interventions state this explicitly.
EXAMPLE: Bortezomib in HD trial
Concomitant medication
In addition to bortezomib, patients will take dexamethasone 20 mg p.o. on every treatment day
(day 1, 4, 8, 11).
8.8
Study Drug / Medical Device Accountability
(ICH/E6 6.4.7; AGEK Checklist 2, item 1; SPIRIT 11c)
ICH: Accountability procedures for the investigational product(s), including the placebo(s) and
comparator(s), if any.
Provide plans of accurate and adequate records maintenance from shipment to the sites until return or
disposal including the physical location, dates (receipt, expiry, use, return), lot/batch number and quantities
(received, used, destroyed).
8.9
Return or Destruction of Study Drug / Medical Device
(AGEK Checklist 2, item 1; SPIRIT 11c)
Provide a statement of the procedures for final reconciliation at the end of the study and whether the product
is shipped back to Sponsor or destroyed.
For medical devices already in use at the hospital "return or destruction" are according to standard procedures
and mentioning this in the protocol is enough (no details needed).
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Document1
55 | 82
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9. STUDY ASSESSMENTS
(ICH/E6 6.7, 6.8; AGEK 6, 7; SPIRIT #18a)
Describe procedures, measurements, collection, storage of samples taken, etc.
All study-related/-mandated procedures i.e. not done routinely in clinical practice should be marked
clearly e.g. with a star and explained in footnote.
9.1
Study flow chart(s) / table of study procedures and assessments
Provide a detailed graph, chart or table of flow of the study and for the study participant ("assessment
schedule") with what is measured and how, grouped according to primary, secondary and/or other endpoints.
Include the allowed time frames for each visit. The flow chart should comprise all study procedures during the
whole course of the study, not only the assessed endpoints. It may be referred to section “STUDY
SCHEDULE” in case all these details are provided there. It is recommended that the flow chart is repeated
here.
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Document1
56 | 82
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Study assessments overview
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Document1
57 | 82
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9.2
Assessments of outcomes
ICH: Specification of the efficacy parameters. Specification of safety parameters.
Describe for each endpoint (if applicable) what variables will be assessed/observed and how it will be done
(eg, questionnaires, laboratory tests), including any related processes to promote data quality (eg, duplicate
measurements, training of assessors; medical device: equipment to be used and arrangements for
maintenance and calibration) Provide the rationale or justification to use certain methods and not others etc.
Define the time windows allowed.
The following assessments have to be performed every month during treatment.

List what elements of the clinical examination are required

Describe specific clinical examinations in detail
9.2.1
Assessment of primary outcome
ICH: Methods and timing for assessing, recording, and analysing of efficacy & safety parameters.
What will be assessed, when and how (e.g., The primary outcome, change of diastolic blood pressure at Day
21, will be measured as first item of the study visit. The equipment xy will be used. The participant should be
in supine position and 5 minutes at rest. In case the measurement needs to be repeated, it should be waited
for at least 10 minutes. A repeated measurement needs to be recorded in the CRF.)
9.2.2
Assessment of secondary outcomes
ICH: Methods and timing for assessing, recording, and analysing of efficacy & safety parameters.
What will be assessed, when and how (e.g., The secondary outcome, change of diastolic and systolic blood
pressure at the various time-points, will be measured as described for the primary endpoint.)
9.2.3
Assessment of other outcomes of interest
ICH: Methods and timing for assessing, recording, and analysing of efficacy & safety parameters.
What will be assessed, when and how (e.g., demographic characteristics, physical examination, Quality of life,
biomarkers: describe sample kind, preparation, storage (in biobanks and the appropriate procedure with
separate PIC) or destruction, shipment to other labs/ countries if applicable. This should be a practical
instruction; regulatory aspects are described in chapter 12.7; pharmacokinetic parameters: describe condition
of participant (e.g., fasting, x hours after treatment with study drug), time-points of sampling, size of sample
taken, sample processing, storage, shipping, substances to be analysed, how their concentration is measured,
validation of analytical system.)
9.2.4
Assessment of safety outcomes
ICH E6 6.8: Specification of safety parameters. The methods and timing for assessing, recording, and
analysing safety parameters
What will be assessed, when and how.
9.2.4.1
Adverse events
Recording of adverse event information, what information needs to be collected: time of onset, duration,
resolution, action to be taken, assessment of intensity, relationship with study treatment; refer to Section 10 for
AE definition and procedures; define specific process to ask the participant at the visits about adverse events,
collection of spontaneous reports.

List what elements of the history and clinical examination are required

Describe specific clinical examinations in detail
Short study title, Version #.## (dd.mm.yyyy)
2 | 82
Based on RCTProtocolTemplate_CTUBern_v01_st.docx
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Pre-existing diseases present prior to administration of study intervention, will be documented as concomitant
diseases as part of participant history in the CRF. Any disease newly occurring or increasing in severity during
the course of the trial will be documented as an AE.
The most up to date version of the CTU Bern SOP "Safety reporting in clinical studies with drugs
(CS_CI_SOP-01)" (current version: 01, 1.1.2013) will be used to manage adverse event related issues in this
trial.
If the SOP is not used for the trial provide all required details. The SOP might be a starting point.
The SOP contains:

Definitions of terms

Instructions on assessing adverse events

Instructions for handling, documenting, and reporting adverse events

Guidance on responsibilities

Guidance on annual safety reports
Provide details about study specific surveillance of adverse events: passive ("Watch and wait" approach with
spontaneous reports by participants), unspecific active, specific active. Take into consideration already known
and clinically relevant harms.
Patients will regularly be assessed for development of adverse events during study visits. The safety
office/sponsor will be timely informed about all serious adverse events as defined in the SOP mentioned
above. The following potential adverse events will be actively monitored during this study (Ensure that this
section agrees with study assessments in section Error! Reference source not found.):

List all laboratory assessments

List all other tests/questionnaires that apply
The instructions for rapid notification of SAEs as outlined in the SOP mentioned above do not apply for the
following events:

Adverse reactions listed in the package insert or investigator's brochure

List any other adverse events
For the purpose of this study the following adverse events will be handled like a SUSAR (regarding reporting
requirements) as described in the SOP mentioned above:

List all adverse events that require rapid notification (which are not necessarily a SAE/SUSAR)
The flow chart on the next page shows graphically the process of expedited safety reporting.
Short study title, Version #.## (dd.mm.yyyy)
3 | 82
Based on RCTProtocolTemplate_CTUBern_v01_st.docx
Notification Procedures for Clinical Trials with Investigational Medicinal Products
Local or Coordinating Investigator
Occurence of
Adverse Event
Phase
Document for trials Cat C
& Cat B (if requested)
irrespective of causality
Summary in
Annual Safety Report
No → AE
No
Multicentre trials
Report to LEAD EC
® within 7 days if fatal
® within 15 days all other
SUSARs
Life
Threatening?
Yes → SAE
Serious?
No
Yes
Fatal?
Yes → SAE
Yes
Swiss trial
site?
Multicentre trials
Report to LEAD EC
® within max 7 days
24 h
to sponsor
Coordinating
Investigator
Yes
Coordinating
Investigator
Report within
Report to LOCAL EC within
® within 7 days if fatal
® within 15 days all other
SUSARs
Yes
1
Report to LOCAL EC
® within max 7 days
Swiss trial
site?
Serious?
Yes
unlikely,
unclassifiable
No SUSAR
Report to all
participating
investigators
Related?
Sponsor
certainly, probably, possibly
No
Unexpected?
Yes
SUSAR
Summary in
Annual Safety Report
9.2.4.2
No
Swiss trial
site?
Yes
Report to Swissmedic: for Cat C & B Trials
® within 7 days if fatal
® within 15 days all other SUSARs
Laboratory parameters
Specify laboratory parameters to be assessed; define when abnormal laboratory parameters will be considered
as adverse events, define time-points of assessment; describe sampling if deviating from hospital routine; specify
tests to be used (e.g., for pregnancy: blood, urine; urinalysis); describe analysis of samples: local or abroad, if
abroad, describe procedure for shipment, storage until shipment; if not yet known, refer to instruction to be written
for the study team and to be part of the study manual.

List all laboratory diagnostics

List all imaging diagnostics

Chest X-ray1
9.2.4.3
Vital signs
Describe how and when they will be assessed (e.g., heart beat, blood pressure, body temperature, ECG) (e.g,, in
supine position after 5 minutes resting).
9.2.5
Assessments in participants who prematurely stop the study
Describe follow-up procedures and assessments in participants who are withdrawn from the study prematurely
(e.g., recording of adverse events, physical examination, laboratory parameters, vital signs). Define follow-up
period; refer to Section 10 for procedures for participants who prematurely stop the study.
The following assessments have to be performed at the end of treatment or if a patient is withdrawn prematurely
from treatment.
1
This assessment is trial-specific
Study ID, Version xx of date (DD/MM/YYYY)
Page 4 of 82
9.3
Procedures at each visit
Provide a verbal description of procedures at each visit according to study phase: e.g. screening, baseline, visits
during intervention, close-out visit, follow-up visits. Includes additional tasks as scheduling of next visit,
distribution of study medication, what is not a measurement to be described (bulleted list).
9.3.1
Split into subtitles by type of visit
(e.g. Screening visit, Day (e.g., -10 to 0): List all exams/tests and other actions to be performed
9.3.2
Split into subtitles by type of visit
(e.g. Visit 1, Baseline (Day e.g., 1): List all exams/tests, actions to be performed according to flow chart (9.1)
including also e.g., Dispense of trial medication, Scheduling of next visit)
Baseline assessments should be performed within 14 days of randomization but before any treatment.
9.3.3
Split into subtitles by type of visit
(e.g. Visit 2-5 (± indicate the window), if they are identical, otherwise describe each visit separately)
The following assessments have to be performed every month during treatment.
Clinical examination

List what elements of the clinical examination are required

Describe specific clinical examinations in detail
Laboratory diagnostics

List all laboratory diagnostics
Imaging diagnostics

List all imaging diagnostics
The following assessments have to be performed at the final visit ($$$ years/months after end of treatment).
Example: If a patient withdraws consent after the end of treatment investigators will make every reasonable effort
to keep each patient on the study until all assessments have been performed. When a patient still wants to end
the study prematurely, the date and reason for early discontinuation will be noted in the source document and the
appropriate portion of the CRF. Investigators will make any reasonable effort to collect and report all end-of-study
evaluations in these patients. Patients should be informed that data collected until the withdrawal will be kept in
the study database and used for analysis.
Study ID, Version xx of date (DD/MM/YYYY)
Page 5 of 82
10. SAFETY
(ClinO Art. 37-43; ICH/E6 6.8; ISO14155 8.2.5, A.14; AGEK 4.1; SPIRIT # 22, 30)
Describe plans for collecting, documenting, assessing, reporting, and managing solicited and spontaneously
reported adverse events and other unintended effects of trial interventions or trial conduct.
Fill the section relevant to your study, e.g. either drug studies (10.1) or device studies (10.2).
10.1 Drug studies
The Sponsor’s SOPs provide more detail on safety reporting.
During the entire duration of the study, all adverse events (AE) and all serious adverse events (SAEs)
are collected, fully investigated and documented in source documents and case report forms (CRF).
Study duration encompassed the time from when the participant signs the informed consent until the
last protocol-specific procedure has been completed, including a safety follow-up period.
Note: The new law on clinical research (ordinance ClinO) does not require the documentation of AEs for Category
A drug trials. For Category B trials the documentation of AEs is only mandatory if this is written in the study
protocol or requested from the authorities. The documentation of SAEs is mandatory for all categories. Please
adapt above sentence according to the categorisation and your needs.
10.1.1 Definition and assessment of (serious) adverse events and other safety related events
ICH: Procedures for eliciting reports of and for recording … adverse event and intercurrent illnesses.
An Adverse Event (AE) is any untoward medical occurrence in a patient or a clinical investigation
participant administered a pharmaceutical product and which does not necessarily have a causal
relationship with the study procedure. An AE can therefore be any unfavourable and unintended sign
(including an abnormal laboratory finding), symptom, or disease temporally associated with the use of
a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
ICH E6 1.2
A Serious Adverse Event (SAE) is classified as any untoward medical occurrence that:





results in death,
is life-threatening,
requires in-patient hospitalization or prolongation of existing hospitalisation,
results in persistent or significant disability/incapacity, or
is a congenital anomaly/birth defect.
In addition, important medical events that may not be immediately life-threatening or result in death, or
require hospitalisation, but may jeopardise the patient or may require intervention to prevent one of the
other outcomes listed above should also usually be considered serious. ICH E2A
Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm,
blood dyscrasias or convulsions that do not result in hospitalisation, or development of drug dependency or drug
abuse.
SAEs should be followed until resolution or stabilisation. Participants with ongoing SAEs at study
termination (including safety visit) will be further followed up until recovery or until stabilisation of the
disease after termination.
Assessment of Causality
Both Investigator and Sponsor-investigator make a causality assessment of the event to the study drug,
based on the criteria listed in the ICH E2A guidelines:
Relationship
Description
Definitely
Temporal relationship
Improvement after dechallenge*
Recurrence after rechallenge
(or other proof of drug cause)
Probably
Study ID, Version xx of date (DD/MM/YYYY)
Temporal relationship
Page 6 of 82
Improvement after dechallenge
No other cause evident
Possibly
Temporal relationship
Other cause possible
Unlikely
Any assessable reaction that does not fulfil the above conditions
Not related
Causal relationship can be ruled out
*Improvement after dechallenge only taken into consideration, if applicable to reaction
Note that other categories can be used. However, a definition has to be provided in the protocol.
Unexpected Adverse Drug Reaction
An “unexpected” adverse drug reaction is an adverse reaction, the nature or severity of which is not
consistent with the applicable product information (e.g. Investigator’s Brochure for drugs that are not yet
approved and Product Information for approved drugs, respectively). ICH E2A
Suspected Unexpected Serious Adverse Reactions (SUSARs)
The Sponsor-Investigator evaluates any SAE that has been reported regarding seriousness, causality
and expectedness. If the event is related to the investigational product and is both serious and
unexpected, it is classified as a SUSAR.
Note: In case of double-blinded studies, unblinding is needed in order to determine a SUSAR.
Assessment of Severity
Describe the severity grading scale in use for this study, depending on the type of study and disease, the grades
for severity described in the “Common Terminology Criteria for Adverse Events CTCAE Version x” terminology
may be used and should be referred to here. Other definitions and grades are possible and shall be provided in
the protocol (e.g. grading scale with explanation or reference to source).
10.1.2 Reporting of serious adverse events (SAE) and other safety related events
(ClinO Art. 37)
ICH: Procedures for … reporting adverse event and intercurrent illnesses.
Describe how, by whom and in what time frame the serious and other reportable adverse events (safety signals,
pregnancies if applicable, etc.) are reported. This should also define the reporting Principal Investigator to
Sponsor in case of a multicentre trial, when the Sponsor and the Principal Investigator are not the same person.
Important note concerning all following sections of this chapter 10.1.2: add, respectively adapt to other local
requirements in case of international studies.
Reporting of SAEs
All SAEs must be reported immediately and within a maximum of 24 hours to the Sponsor-Investigator
of the study. The Sponsor-Investigator will re-evaluate the SAE and return the form to the site.
SAEs resulting in death are reported to the local Ethics Committee (via local Investigator) within 7 days.
For multicentre studies, add that:
The other in the trial involved Ethics Committees receive SAEs resulting in death in Switzerland via
Sponsor-Investigator within 7 days.
Exemptions from expedited reporting may be possible if the SAE is either a clear result of the underlying disease
or well known and described in the currently approved product information (mainly for phase IV studies). Please
define those SAEs that are exempted from expedited reporting.
Reporting of SAEs or other safety relevant events to the Marketing Approval Holder (MAH) of the drug(s) may be
necessary. If so, this should be described either in this section or in the contract with the MAH.
Reporting of SUSARs
Study ID, Version xx of date (DD/MM/YYYY)
Page 7 of 82
A SUSAR needs to be reported to the local Ethics Committee (local event via local Investigator) and to
Swissmedic for category B and C studies (via Sponsor-Investigator) within 7 days, if the event is fatal,
or within 15 days (all other events).
In multicentre studies the following should be added:
The Sponsor-Investigator must inform all Investigators participating in the clinical study of the
occurrence of a SUSAR. All in the trial involved Ethics Committees will be informed about SUSARs in
Switzerland via Sponsor-Investigator according to the same timelines.
Reporting of Safety Signals
All suspected new risks and relevant new aspects of known adverse reactions that require safety-related
measures, i.e. so called safety signals, must be reported to the Sponsor-Investigator within 24 hours.
The Sponsor-Investigator must report the safety signals within 7 days to the local Ethics Committee
(local event via local Investigator) and to Swissmedic in case of a category B or C study.
In multicenter studies the following should be added:
The Sponsor-Investigator must immediately inform all participating Investigators about all safety signals.
The other in the trial involved Ethics Committees will be informed about safety signals in Switzerland via
the Sponsor-Investigator.
Reporting and Handling of Pregnancies
If applicable, describe the handling and reporting duties in case of a pregnancy during the study
Pregnant participants must immediately be withdrawn from the clinical study. Any pregnancy during the
treatment phase of the study and within 30 days after discontinuation of study medication will be reported
to the Sponsor-Investigator within 24 hours. The course and outcome of the pregnancy should be
followed up carefully, and any abnormal outcome regarding the mother or the child should be
documented and reported.
This section should be adapted based on the type of study and depending on the study drug.
Periodic reporting of safety
Describe any specific periodic safety (and other) reporting duties according to local legislation to the competent
authorities (CEC, Swissmedic, foreign CA if applicable, others if applicable).
An annual safety report is submitted once a year to the local Ethics Committee via local Investigator and
to Swissmedic in case of a category B or C study via Sponsor-Investigator.
For multicentre studies the annual safety report contains information from all sites including information from sites
outside of Switzerland. The Sponsor-Investigator prepares it, and then submits it to the participating Investigators.
The participating Investigators submit it to the local committees.
In clinical trials with radiopharmaceuticals the FOPH requests a final report within one year after study termination
regarding all aspects of radiation protection (see ClinO Art. 44). Exempted are routine examinations with
approved radiopharmaceuticals.
10.1.3 Follow up of (Serious) Adverse Events
(ICH/E6 6.8.4; SPIRIT #30)
ICH: The type and duration of the follow-up of subjects after adverse events.
Describe the follow up of participants terminating the study (either regularly or prematurely) with reported ongoing
SAE, or any ongoing AEs of laboratory values or of vital signs being beyond the alert. Describe procedures: when
and how and what is done and documented. Describe efforts to be done in case of loss to follow up.
Study ID, Version xx of date (DD/MM/YYYY)
Page 8 of 82
10.2 Medical Device Category C studies
All adverse events (AE) including all serious adverse events (SAE) are collected, fully investigated
and documented in the source document and appropriate case report form (CRF) during the entire study
period, i.e. from patient’s informed consent until the last protocol-specific procedure, including a safety
follow-up period. Documentation includes dates of event, treatment, resolution, assessment of
seriousness and causal relationship to device and/or study procedure.
Specify here how the information on AEs is systematically collected (e.g. “by clinical safety assessment and/or
safety lab at the regular study visits”, as applicable and clinically justified in the context of the specific protocol).
Also specify here the follow-up period, if applicable (also in case of premature study withdrawal of participant). If
no such safety follow-up is needed, please specify and justify.
List here foreseeable adverse events and anticipated adverse device effects, together with their likely incidence,
mitigation or treatment.
10.2.1 Definition and Assessment of (Serious) Adverse Events and other safety related events
(MD: ISO 14155)
Adverse Event (AE)
Any untoward medical occurrence, unintended disease or injury or any untoward clinical signs (including
an abnormal laboratory finding) in participants, users or other persons whether or not related to the
investigational medical device [ISO 14155: 3.2].
This includes events related to the investigational device or the comparator and to the procedures involved. For
users or other persons this is restricted to events related to the investigational medical device.
Adverse Device Effect (ADE)
Adverse event related to the use of an investigational medical device [ISO 14155: 3.1].
This includes any adverse event resulting from insufficient or inadequate instructions for use, deployment,
implantation, installation, operation, or any malfunction of the investigational medical device. This includes any
event that is a result of a use error or intentional misuse.
Serious Adverse Event (SAE)
Adverse event that:



results in death, or
led to a serious deterioration in health that either:
results in a life-threatening illness or injury, or
results in a permanent impairment of a body structure or a body function, or
required in-patient or prolonged hospitalisation, or
results in medical or surgical intervention to prevent life threatening illness, or
led to fetal distress, death or a congenital abnormality or birth defect. [ISO 14155: 3.37].
This includes device deficiencies that might have led to a serious adverse event if a) suitable action had not been
taken or b) intervention had not been made or c) if circumstances had been less fortunate. These are handled
under the SAE reporting system. A planned hospitalisation for pre-existing condition, or a procedure required by
the protocol, without a serious deterioration in health, is not considered to be a serious adverse event.
Device deficiency
Inadequacy of a medical device related to its identity, quality, durability, reliability, safety or performance,
such as malfunction, misuse or use error and inadequate labelling [ISO 14155: 3.15].
Health hazards that require measures
Findings in the trial that may affect the safety of study participants and, which require preventive or
corrective measures intended to protect the health and safety of study participants.
Causal Relationship of Adverse Events
A causal relationship towards the medical device or study procedure should be rated as follows:

Not related: The event is definitely not associated with device application or with study
Study ID, Version xx of date (DD/MM/YYYY)
Page 9 of 82


procedures; a relationship can be ruled out.
Possibly related: The relationship between device application or study procedures and the
event is possible, but other causes cannot definitely be ruled out.
Related: The event is definitely associated with device application or study procedures.
Device deficiencies that might have led to an SAE are always related to the medical device.
10.2.2 Reporting of (Serious) Adverse Events and other safety related events
Describe how, by whom and in what time frame the serious and other reportable adverse events (health hazards,
pregnancies if applicable, etc.) are reported. This should also define the reporting PI to Sponsor in case of a
multicentre trial, when the sponsor and the PI are not the same person.
Important note concerning all following sections of this chapter 10.2.2: add, respectively adapt to other local
requirements in case of international studies.
Reporting to Sponsor-Investigator:
The following events are to be reported to the Sponsor-Investigator within 24 hours upon becoming
aware of the event:



All SAEs
Health hazards that require measures
Device deficiencies
The Sponsor-Investigator will evaluate SAEs with regard to causality and seriousness. Device
deficiencies are assessed regarding their potential to lead to an SAE.
Pregnancies
Note: Depending of the study, reporting of pregnancies may not be necessary.
If reporting is needed, include in the protocol how pregnancies will be reported (usually within a maximum of 24
hours to the Sponsor-Investigator), and how occurrence of pregnancy will be handled in the study (patient is
withdrawn, outcome of the pregnancy should be followed-up, etc). Details will depend on the type of study.
Reporting to Authorities:
In Category C studies it is the local Investigator’s responsibility to report serious adverse events in
Switzerland which are


related or possibly related to the medical device under investigation
related or possibly related to study procedures
within 7 days to the local Ethics Committee. The Sponsor-Investigator reports within the same timeline
to Swissmedic (incl. events from abroad).

Health hazards that require measures are reported within 2 days
Note: For multicentre studies add (to be deleted for monocentre studies):
All in the trial involved other Ethical Committees receive all mentioned reportable SAEs and health
hazards having occurred in Switzerland via the Sponsor-Investigator within the same timeline. All
participating investigators are informed regarding the occurrence of a health hazard.
Periodic safety reporting
In Category C studies a yearly safety update-report is submitted by the Investigator to the Ethics
Committee and by the Sponsor-Investigator to Swissmedic.
10.2.3 Follow up of (Serious) Adverse Events
(SPIRIT #30)
Describe the follow up of participants terminating the study (either regularly or prematurely) with reported ongoing
SAE, or any ongoing AEs of laboratory values or of vital signs being beyond the alert. Describe procedures: when
and how and what is done and documented. Describe efforts to be done in case of loss to follow up.
Study ID, Version xx of date (DD/MM/YYYY)
Page 10 of 82
10.3 Medical Device Category A studies
10.3.1 Definition and Assessment of safety related events
Health hazards that require measures
Findings in the trial that may affect the safety of study participants and which require preventive or corrective
measures intended to protect the health and safety of study participants.
Important note concerning all following sections of this chapter 10.3: add, respectively adapt to other local
requirements in case of international studies.
10.3.2 Reporting of Safety related events
Reporting to Sponsor-Investigator:
Health hazard that require measures are reported to the Sponsor-Investigator within 24 hours upon
becoming aware of the event:
Pregnancies
Depending of the study, reporting of pregnancies may not be necessary. If reporting is needed, include in the
protocol how pregnancies will be reported (usually within a maximum of 24 hours to the Sponsor-Investigator),
and how occurrence of pregnancy will be handled in the study (patient is withdrawn, outcome of the pregnancy
should be followed-up, etc). Details will depend on the type of study.
Reporting to Authorities:
In Category A studies it is the Investigator’s responsibility to report to the local Ethics Committee

Health hazards that require measures within 2 days
For multicentre studies add (to be deleted for monocentre studies):
All other in the trial involved Ethics Committees receive health hazards having occurred in Switzerland
via the Sponsor-Investigator within the same timeline. All participating investigators are informed
regarding the occurrence of a health hazard.
The Sponsor-Investigator will notify Swissmedic of reportable events, based on the national regulations
for materiovigilance procedures.
Study ID, Version xx of date (DD/MM/YYYY)
Page 11 of 82
11. STATISTICAL METHODS
(ICH/E6 6.9; AGEK 8; SPIRIT # 14, 20)
Statistical considerations
ICH: A description of the statistical methods to be employed, including timing of any planned interim
analysis(ses).
Describe the statistical considerations done for the study, the level of significance that will be used.
11.1 Hypothesis
If a Null Hypothesis is tested, state explicitly both Null and Alternative Hypotheses in terms of the primary
endpoint and justify them in regard of the participant population and dose. The stated hypotheses have to be
used in the determination of Sample Size. Relate these hypotheses to the study objectives.
If hypothesis testing is not used, then discuss the manner in which the approach that will be used (e.g. Bayesian
methods) will address objectives.
11.2 Determination of Sample Size
ICH: The number of subjects planned to be enrolled. In multicentre trials, the numbers of enrolled subjects
projected for each trial site should be specified. Reason for choice of sample size, including reflections on
(or calculations of) the power of the trial and clinical justification.
Provide the estimated number of participants for each study site and study arm (if applicable) needed to achieve
the objective, how it was determined, including clinical and statistical assumptions supporting any sample size
calculations, the power of the trial, the type I error (one- or two-sided) and the related risk, the clinical justification.
Provide the number of participants to be enrolled (including a projection per study site).
Describe sample size calculation and feasibility of recruitment. A justification of sample size requires details on: 1)
Outcome(s) on which sample size calculation is based; 2) Null hypothesis; 3) level of type I error; 4) level of type
II error; 5) minimal clinically relevant difference; 6) allocation ratio; 7) underlying statistical test/methods; 8)
software used for sample size calculation; 9) corrections for drop-outs/withdrawals; 10) Assumptions of any
parameter used
EXAMPLE: Magpie trial
Sample size estimates
Sample size estimates For women with severe pre-eclampsia the risk of convulsions is around
1%. To demonstrate a halving in this risk would require 14,000 women (alpha 0.05, beta 0.1).
The aim is therefore to recruit 14,000 women. The trial may include women with a lower seizure
risk and, if this was 0.75%, the power to demonstrate a halving would then be 80%. Most women
(90%) are likely to be randomised before delivery and, if total mortality for the babies was 12%,
this would give a power of 90% to detect a 15% proportional reduction to 10.2% (alpha 0.05). If
total mortality for the babies was reduced from 10% to 8.5% (15% reduction), the power would
be 80% (alpha 0.05).
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EXAMPLE: INIS trial
Sample size
Table 4 shows positive blood culture rates (including probable contaminants) in 3,963
consecutive infants of all birthweights admitted to a randomly selected, nationally representative
cohort of 54 UK neonatal units between 1st March 1998 and 4th September 1998 in a study of
organisation and outcomes of neonatal care funded by the NHS Executive6.
Table 4
Number with
positive cultures
Mortality
(all causes)
Number with
negative cultures
Mortality
(all causes)
204 / 3,963 (5%)
16 / 204 (8%)
3,759 / 3,963 (95%)
95 / 3,759 (2.5%)
Among VLBW infants with positive blood cultures, mortality was 14%. In a recent North American
cohort, mortality in VLBW infants with septicaemia was 21%7. Assuming combined rates of
mortality and major morbidity of 10-20% for all infants and 20-30% for VLBW infants, Table 5
outlines estimated sample sizes.
Table 5
Mortality or
major
morbidity
in control
group
Mortality or
major
morbidity
in IVIG group
Relative
risk
reduction
30%
26%
30%
Total sample size required to
detect difference with 95%
confidence
80% power
90% power
13%
4,052
5,392
25%
17%
2,580
3,428
30%
20%
33%
626
824
25%
21%
16%
3,572
4,748
25%
20%
20%
2,266
3,006
25%
15%
40%
540
708
20%
16%
20%
2,994
3,972
20%
15%
25%
1,890
2,502
20%
12.5%
37.5%
810
1,066
15%
12%
20%
4,204
5,582
15%
10%
33%
1,450
1,914
12%
9%
25%
3,408
4,516
10%
7.5%
25%
4,166
5,524
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EXAMPLE: INIS trial
Feasibility
About 5,000 infants will be needed to demonstrate moderate reductions in mortality or survival
with major developmental delay with adequate power. Over a three year recruitment period,
assuming that 7-10% of all admissions are diagnosed with clinical sepsis and considered eligible
for recruitment, 150 NICUs with an average of 300 admissions per year will be required to
achieve the recruitment target, assuming a 40-50% rate of recruitment of eligible infants.
Neonatal units will initially be recruited in the UK, Australia and New Zealand. A census of all 186
UK neonatal intensive care units (NICUs) and 60 special care baby units in 199662 (which is a
100% response rate) found that the median number of admissions per year per NICU was 317. If
a broadly representative sample of about half all UK NICUs and SCBUs participate, then over
50% of the projected recruitment rate for the trial will be possible within the UK, leaving the
additional 50% to be recruited from the rest of the world. This study reflects the philosophy that
the only practicable way to achieve comparisons which are sufficiently large to minimise the risk
of being seriously misled by the play of chance is to design trials that are extremely simple and
flexible63. Experience in the OSIRIS64 and MRC ORACLE study48 49 suggest that a large, simple
trial of this scale of a potentially important intervention supplied free of charge to participating
centres is feasible. Furthermore, systematic reviews of RCTs of IVIG therapy in neonatal sepsis
suggest a substantial reduction in mortality. This contrasts with the systematic reviews of RCTs
of antibiotics in threatened preterm birth which led to the ORACLE study, as these showed no
evidence of a difference in neonatal mortality. This preliminary evidence that IVIG may reduce
mortality may further enhance the appeal of the study.
The estimate of the incidence of the outcome (the event rate) for the trial is imprecise, particularly
as the threshold at which clinicians will enter patients cannot be estimated. If clinicians enter
babies where the likelihood of serious sepsis is lower then the event rate will also be lower. If
clinicians restrict entry to only those babies who are very sick, then the event rate will be high.
Either of these two scenarios is reasonable because it will define a population to which the trial
result can be generalised. However, it does mean that until the trial has recruited sufficient
numbers of babies it will not be possible to determine the optimum trial sample size with any
certainty. As a consequence the trial sample size currently represents the minimum size
desirable. Assuming the trial recruits for three years, the maximum number of babies which can
be recruited during this time will be recruited and it is possible that this number may exceed
5,000. During recruitment to the trial the accumulating data will be seen by an independent Data
Monitoring and Ethics Committee at least once per year (see above) and they will advise the
Trial Steering Committee whether the trial has answered the clinical question being addressed. If
not, the trial will continue to recruit until 5,000 babies have been recruited, or until funding is
exhausted.
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11.3 Statistical criteria of termination of trial
ICH: A description of the "stopping rules" or "discontinuation criteria" for individual participants, parts of
trial and entire trial.
Describe the criteria for the termination of the trial or the stopping rules.
11.4 Planned Analyses
ICH: A description of the statistical methods to be employed, including timing of any planned interim
analysis(ses).
Make brief statements of the analyses that are planned, the methods and types and which variables and with
what data sets and when (a detailed statistical analysis plan may be written as a separate document after
finalisation of protocol and may be referred to this document, e.g “statistical analysis plan”)
11.4.1 Datasets to be analysed, analysis populations
ICH: The selection of subjects to be included in the analyses (e.g., all randomized subjects, all dosed
subjects, all eligible subjects, evaluable subjects).
Describe the analysis populations, evaluation groups (intention to treat, per protocol, etc.) and data sets to be
used for analysis and methods for any additional analyses (eg, subgroup and adjusted analyses)
Example: The main analysis will be based on all randomized patients regardless of whether they actually received
the allocated intervention or not or any other protocol deviations. Patients will be analyzed in the group they were
randomized regardless of any cross-overs (intention-to-treat principle).
Provide a definition of the intention-to-treat analysis set for this trial.
Example: Secondary analyses will allow for a per-protocol analysis where only patients will be included who
actually received the allocated product for at least (give minimum amount of intervention received e.g. two weeks)
and other details that need to be fulfilled (e.g. the number of follow-up visits attended).
Example: All analyses will be done using provide details on statistical package(s) that will be used.
Example: All confidence intervals will relate to the 95% level and the two-sided significance level will be set at
0.05. No adjustment for multiple testing will be done.
Example: A detailed statistical analysis plan will be developed before the final analysis describing the exact
procedures including assessments of model fit and consequences.
11.4.2 Primary Analysis
Describe the intended primary analysis that will be done, when and how and by whom it will be done,
Describe how the primary outcomes will be analysed e.g. statistical model. Describe how missing data will
handled.
11.4.3 Secondary Analyses
Describe the intended secondary analysis that will be done, when and how and by whom it will be done.
Describe the intended subgroup analyses, if applicable, that will be done, when and how and by whom they will
be done, add hypothesis related to each subgroup.
Describe how the secondary analyses will be done e.g. statistical model.
11.4.4 Interim analyses
ICH 6.9.1: ...... including timing of any planned interim analysis(ses).
Describe the intended interim analysis that will be done, why, when and how and by whom it will be done, taking
into consideration their purpose, frequency, timing, scope, statistical procedures, Data Monitoring Committee
involvement, and stopping guidelines. Explain the methods that will be used to adjust for interim analyses, or give
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a rationale for why adjustment is not necessary.
No interim analysis is foreseen in this study.
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11.4.5 Safety analysis
Describe the analysis of the safety parameters that will be done, when and how and by whom will it be done.
11.4.6 Deviation(s) from the original statistical plan
(ICH/E6 6.9.6)
ICH: Procedures for reporting any deviation(s) from the original statistical plan (any deviation(s) from the
original statistical plan should be described and justified in protocol and/or in the final report, as
appropriate).
Describe how any deviation(s) from the planned analyses will be justified and reported.
11.5 Handling of missing data and drop-outs
(ICH/E6 6.9.5; AGEK 8.5; SPIRIT 20c)
ICH: Procedure for accounting for missing, unused, and spurious data.
Describe how missing data will be handled (e.g. multiple imputation, last observation carried forward, complete
case analysis…) and if drop-outs are replaced. If sensitivity analyses are planned, specify them.
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12. QUALITY ASSURANCE AND CONTROL
(ICH/E6 6.11, 6.13; AGEK 12; SPIRIT #19, 23, 27)
ICH: Quality Control and Quality Assurance Procedures
Describe how quality is assured and controlled. The Sponsor is responsible for implementing and maintaining
quality assurance and quality control systems with written SOPs and Working Instructions, at all sites in case of
multicentre studies. The PI is responsible for proper training of all involved study personnel.
Example: A multilevel data validation/monitoring plan is conceived in order to guarantee the correctness and
consistency of the data in the CRFs and database.
12.1 Data handling and record keeping / archiving
(ClinO, Art. 18, 45, 57, 62; ICH/E6 6.13; AGEK 12; SPIRIT #19, 27)
ICH: Data Handling and Record Keeping
Describe how data are handled and that all study related documents are archived (essential documents and site
documents)
Example: At each site an Investigator Site File will be maintained including at least the following
documents/information:

Signed protocol and amendments

Sample case report forms (CRF)

Current informed consent form and all revisions

Current patient information and all revisions

Any other written information

Financial aspects of the study

Insurance statement

All signed agreements/contracts

Dated, documented approval of ethics committee and regulatory authorities

Signed CVs of all investigators and any study personnel (update regularly)

Instructions for handling of investigational product and study related materials

Monitoring reports

-
Study initiation report
-
Follow-up letters of on-site visits
-
Study close out report
Relevant communication
-
Letters
-
Meeting notes
-
Notes of telephone calls

Signed informed consent forms

Signed, dated and completed case report forms if applicable

SAE reporting

Notification by sponsor of safety information

Interim and annual reports to ethics committee and regulatory authorities
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
Subject screening log

Subject identification code list

Subject enrolment log

Investigational product accountability

Authorisation/signature sheet

Record of retained body fluids/tissue samples

Documentation of investigational product destruction

Clinical study report
12.1.1 Case Report Forms
(ICH/E6 6.4.9)
ICH: The identification of any data to be recorded directly on the CRFs (i.e., no prior written or electronic
record of data), and to be considered to be source data.
Describe how study data is recorded, e.g. with paper or electronic Case Report Forms (p-/e-CRF). For each
enrolled study participant a CRF is maintained. CRFs must be kept current to reflect subject status at each phase
during the course of study. Participants must not be identified in the CRF by name or initials and birth date.
Appropriate coded identification, e.g. participant number must be used (combination of initials and year of birth is
possible).
It should be described who is authorized for which CRF entries and it must be assured that any authorised person
can be identified. If paper CRFs are used, describe how data is entered into an electronic database for analysis
(e.g., double data entry).
Example: All protocol required procedures along with information necessary to report the observations and tests
described in this protocol are recorded in the case report forms (CRFs). CRFs must be completed and signed in a
timely and accurate manner by study site personnel (usually within ten working days after completion of a visit).
Dedicated study personnel at CTU Bern monitors the data entry progress per center to ensure timely data
collection.
Example: All data entered on the CRFs must be documented in a source document. The case report form is not a
source document. If data is directly entered in the CRF without any source document this needs to be explicitly
mentioned in the CRF. All the information on which the entries in the CRF are based must be available in the
patient files e. g. results of laboratory investigations. The investigator must review all CRFs for accuracy and
consistency with the protocol, and sign the CRFs upon completion.
Example: The investigator or a designee is responsible for the presence of the data in the patient file and the
correct entry of the data into the CRF.
Example: After prior agreement, a check of the consistency of data between the patient files, raw data and CRF
as well as with other documents related to the study may be conducted by the responsible authorities and/or by
monitors (inspection/audit/monitoring).
12.1.2 Specification of source documents
(ICH/E6 6.4.9)
ICH: The identification of any data to be recorded directly on the CRFs (i.e., no prior written or electronic
record of data), and to be considered to be source data.
Source data must be available at the site to document the existence of the study participants. Source data must
include the original documents relating to the study, as well as the medical treatment and medical history of the
participant.
Describe what is considered the source documents in the respective study (e.g. demographic data, visit dates,
participation in study and Informed Consent Forms, randomisation number, SAEs, AEs and concomitant
medication, results of relevant examinations. Identify data that are directly recorded in the CRF, which should also
be considered being source data. Also describe where source data are found at the site.
12.1.3 Record keeping / archiving
(ICH/E6 6.13)
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ICH: Data Handling and Record Keeping
All study data must be archived for a minimum of (time according to local legislation) years after study
termination or premature termination of the clinical trial.
Specify location of storage.
IMP: Archiving for 10 years
MD: Archiving for 10 years, in the case of an implantable device 15 years
Example: A copy of the final completed CRFs is retained by the investigator, who must ensure that it is stored
with other study documents, such as the signed informed consent forms, protocol, the investigator’s brochure and
any protocol amendments, in a secure place for 10 (15 for trials with implants) years.
12.2 Data management
(ICH/E2; AGEK 12.2; SPIRIT #19)
Describe plans for data entry, coding, security, and storage, including any related processes to promote data
quality (e.g., double data entry; range checks for data values). In case electronic data capture systems are used,
this chapter shall include a description of procedures for verification, validation and securing the database.
Reference to where details of data management procedures can be found, if not in the protocol.
12.2.1 Data Management System
Describe what system (also software) is being used and who is responsible and how it is tested before the trial
(may include a description of where the system is hosted).
Example: The CRFs in this trial are implemented electronically using a dedicated electronic data capturing (EDC)
system (WebSpirit®/RedCAP). The EDC system is activated for the trial only after successfully passing a formal
test procedure.
Example: All data entered in the CRFs are stored on a Linux/Windows server in a dedicated PostgreSQL
database.
Example: Responsibility for implementing and hosting the EDC system and the database lies with CTU Bern.
12.2.2 Data security, access and back-up
Describe who has access to data, how, where and when – and which backup systems are in place (if applicable).
Example: The server hosting the EDC system and the database is kept in a locked server-room. Only the system
administrators have direct access to the server and back-up tapes. A role concept with personal passwords (site
investigator, statistician, monitor, administrator etc.) regulates permission for each user to use the system and
database as he/she requires.
Example: All data entered into the CRFs are transferred to the database using Secure Sockets Layer (SSL)
encryption. Each data point has attributes attached to it identifying the user who entered it with the exact time and
date. Retrospective alterations of data in the database are recorded in an audit table. Time, table, data field,
original value and altered value, and the person are recorded (audit trail).
Example: A multi-level back-up system is implemented. Back-ups of the whole system including the database are
run internally several times per day and on external tapes once a day. The back-up tapes are stored in a secure
place in a different building.
12.2.3 Analysis and archiving
Describe how data are extracted and where they are stored, database status recording, duration and place of
storage (note MD: the archiving period is different for implantable devices).
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Example: At interim (if applicable) and final analyses, data files will be extracted from the database into statistical
packages to be analyzed. The status of the database at this time is recorded in special archive tables.
Example: The study database with all archive tables will be securely stored by CTU Bern for at least 15 years.
The sponsor also keeps the Trial Master File and interim and final reports both in electronic and in hard copy form
for at least 10 (15 in case of implants) years.
12.2.4 Electronic and central data validation
Describe how data are validated.
Example: Data can be entered into the database only after a check of completeness and plausibility. Furthermore,
selected data points are cross-checked for plausibility with previously entered data for that participant.
Example: In addition, data will be extracted from the database regularly to perform central data validation checks
using statistical software packages. Any detected inconsistencies and relevant missing data will be queried at the
respective center.
12.3 Monitoring
(AGEK 12.1; SPIRIT #23)
Describe the regular monitoring visits at the investigator’s site prior to the start and during the course of the study
organised by the Sponsor. Give a description of what data and documents will be monitored. Alternatively the
extent and nature of monitoring activities based on the objective and design of the study can be defined in a study
specific monitoring plan.
Provide a statement that the source data/documents are accessible to monitors and questions are answered
during monitoring.
Example: In order to guarantee a high quality of the study and data retrieval, participating centers may be visited
on site by independent monitors. Data protection rights are respected. All findings and comments are
documented in a monitoring report and communicated to the investigator and to the sponsor. The investigator in
the participating centers supports the monitor in his/her activities.
Example: Before study start (first participant in) a monitoring plan detailing all on-site monitoring related
procedures is developed.
Example: On-site monitoring will be conducted by CTU Bern.
12.4 Audits and Inspections
(ClinO, Art. 58, 59; AGEK 12.1; SPIRIT #23)
Describe the frequency and procedures for auditing trial conduct, if any, and whether the process will be
independent from investigators and the Sponsor. Provide a statement that the study documentation and the
source data/documents are accessible to auditors/inspectors (also CEC and CA) and questions are answered
during inspections. All involved parties must keep the participant data strictly confidential.
Example: A regulatory authority or independent ethics committee may wish to conduct an inspection (during the
study or even after its completion). If an inspection is requested, the investigator must inform the sponsor
immediately that this request has been made. The investigators in the participating sites will support the
inspectors in their activities.
Example: The study sponsor may exclude participating sites/investigators from further participation in the study
because of fraud or non-compliance with the study protocol, ICH-GCP guidelines, or applicable laws.
Example: Study sites or investigators may stop recruiting patients to this study when the investigator deems
inclusion of patients into this study to be no longer ethical for medical or organizational reasons. In this case, the
investigator should give detailed reasons to the study sponsor.
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12.5 Confidentiality, Data Protection
(ClinO, Art. 18, 58; SPIRIT #27, 29)
Data protection; should include the statement that direct access to source documents will be permitted for
purposes of monitoring (12.3), audits and inspections (12.4) (ICHE6, 6.10) and should declare who will have
access to protocol, dataset, statistical code, etc during and after the study (publication, dissemination).
12.6 Storage of biological material and related health data
(ClinO, Art. 18; HVF Art. 28-32; SPIRIT #33)
If applicable, describe how long samples are stored, or state that they are destroyed at the end of the study.
In the event of Biobank storage, confirm that samples or genetic data are only stored with the participants consent
independent from the study.
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13. PUBLICATION AND DISSEMINATION POLICY
(ICH/E6 6.15)
ICH: Publication policy, if not addressed in a separate agreement.
Describe plans to communicate trial results to participants, healthcare professionals, the public, and other
relevant groups (e.g., via publication, reporting in results databases, or other data sharing arrangements),
including any publication restrictions; anticipate for authorship eligibility guidelines and any intended use of
professional writers and, if any plans for granting public access to the full protocol, participant-level dataset, and
statistical code, and the decision to submit the report for publication, including whether who will have ultimate
authority over any of the activities (Medical devices: in addition mention the protection of trade secrets)
Describe whether and how access to the protocol, dataset, and statistical code is enabled.
Example: The final report will present the results of the study, including appropriate tables and figures in the spirit
of an unbiased objectivity. The sponsor will provide the IEC with a summary of the study’s findings, and if
applicable the regulatory authorities with any reports required. The report, or parts of it, may be submitted in the
form of a summary, a synopsis, published article or in some other similar way.
Example: The sponsor assures that all results of this study are published in a peer-reviewed journal in line with
the Declaration of Helsinki {World Medical Association, 2008 #2}. All results relate to all outcomes as defined in
this protocol regardless of the direction or statistical significance. It will be assured that the manuscript follows the
principle of the CONSORT guidelines or any other applicable reporting guideline (www.equator.org). Coauthorship on any of the publications will be based on contribution to the study and manuscript according to the
criteria of the International Committee of Medical Journal Editors {International Committee of Medical Journal
Editors, 2009 #3}.
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14. FUNDING AND SUPPORT
(ClinO, Art. 25i; ICH/E6 6.14; SPIRIT #4)
Provide brief statement of sources and types of financial, material, and other support for the trial. If applicable,
reference to other places or contracts/documents where this information is captured.
14.1 Funding
(ClinO, Art. 25i)
ICH: Financing and insurance if not addressed in a separate agreement.
Provide brief statement of sources and types of financial support for the trial. If applicable, reference to other
places or contracts/documents where this information is captured.
Provide sources and types of financial, material, and other support for the trial
14.2 Other Support
(ClinO, Art. 25i)
ICH: Financing and insurance if not addressed in a separate agreement.
Provide brief statement of sources and types of material and other support for the trial. If applicable, reference to
other places or contracts/documents where this information is captured.
15. INSURANCE
(ClinO Art 12, 13; ICH/E6 6.14, AGEK 10.3; SPIRIT #30)
ICH: ….and insurance if not addressed in a separate agreement.
Provide a statement like "Insurance will be provided by the Sponsor. A copy of the certificate is filed in each
investigator site file and the trial master file."
Category A studies are exempt. Categories B and C of IMP and C of medical devices studies need to document
the guarantee of liability (insurance certificate or equivalent guarantee).
It can be referred here to another place where the document is found, e.g. in Appendix or separate document.
Example: Insurance will be provided by the Sponsor. A copy of the certificate is filed in each investigator site file
and the trial master file.
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16. REFERENCES
(ICH/E6 6.2.7)
ICH: References to literature and data that are relevant to the trial, and that provide background for the trial.
Provide a list of the references cited in the protocol.
1. Declaration of Helsinki, Version October 2013,
(http://www.wma.net/en/30publications/10policies/b3/index.html )
2. International Conference on Harmonization (ICH, 1996) E6 Guideline for Good Clinical
Practice.
(http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step
4/E6_R1__Guideline.pdf )
3. International Conference on Harmonization (ICH, 1997) E8 Guideline: General Considerations
for Clinical Trials
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E8/Step4/E8
_Guideline.pdf)
4. Humanforschungsgesetz, HFG Bundesgesetz über die Forschung am Menschen
(Bundesgesetz über die Forschung am Menschen, HFG) vom 30. September 2011/ Loi
fédérale relative à la recherche sur l’être humain (loi relative à la recherche sur l’être humain,
LRH) du 30 septembre 2011.
(http://www.bag.admin.ch/themen/medizin/00701/00702/07558/index.html?lang=de)
5. Verordnung über klinische Versuche in der Humanforschung (Verordnung über klinische
Versuche, KlinV) vom 20. September 2013 / Ordonnance sur les essais cliniques dans le
cadre de la recherche sur l’être humain (Ordonnance sur les essais cliniques, OClin) du 20
septembre 2013.
(http://www.bag.admin.ch/themen/medizin/00701/00702/12310/index.html?lang=de)
6. Heilmittelgesetz, HMG Bundesgesetz über Arzneimittel und Medizinprodukte
(Heilmittelgesetz, HMG) vom 15. Dezember 2000/Loi fédérale sur les médicaments et les
dispositifs médicaux (Loi sur les produits thérapeutiques, LPT) du 15 décembre 2000.
(http://www.admin.ch/ch/d/sr/8/812.21.de.pdf)
7. ISO 14155:2011 Clinical investigation of medical devices for human subjects -- Good clinical
practice (www.iso.org)
8. ISO 10993 Biological evaluation of medical devices (www.iso.org)
9. WHO, International Clinical Trials Registry Platform (ICTRP) (http://www.who.int/ictrp/en/)
10. xy
11. yz
12. zz
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17. APPENDICES
ICH: (NOTE: Since the protocol and the clinical trial/study report are closely related, further relevant
information can be found in the ICH Guideline for Structure and Content of Clinical Study Reports.)
Please consider well with adding documents here that are very frequently changing, they may be mentioned as
separately provided documents and listed here.
Except for medical devices, the section headings can be renamed accordingly.
1. IMP: IB or SPC
2. Medical Devices: IB (according to ISO 14155)
3. Medical Devices: Assurance of producer
4. Medical Devices: List of norms (vollständig eingehaltene, teilweise eingehaltene)
5. Radiolabelled products: Strahlenschutzverordnung
6. eg List of study sites / PIs
List of countries or centres where data will be collected or reference to where list of study sites can be obtained
7. Other
eg Specific protocols (e.g. MRI)
eg Case Report Form (e.g. CRF)
eg Patient Information and informed consent
Model of consent form and other related documentation given to participants and authorised surrogates and
additional consent provisions for collection and use of participant data and biological specimens in ancillary
studies, if applicable
eg Other material to patients
Model of consent form and other related documentation given to participants and authorised surrogates and
additional consent provisions for collection and use of participant data and biological specimens in ancillary
studies, if applicable
Study flow diagram ..............................................................................................................41
Study assessments overview ................................................................................................ 56
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Study ID, Version xx of date (DD/MM/YYYY)
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